Selective histamine H4 receptor antagonists for the treatment of vestibular disorders

ABSTRACT

The invention relates to Histamine H4 receptor antagonists or inhibitors of Histamine H4 receptor gene expression for the treatment and/or the prevention of vestibular disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/141,652 filed Sep. 9, 2011, which is a national phase applicationunder 35 U.S.C. § 371 of International Application No. PCT/EP2009/067897filed 23 Dec. 2009, which claims priority to European Application No.08306013.7 filed 24 Dec. 2008. The entire text of each of theabove-referenced disclosures is specifically incorporated herein byreference without disclaimer.

FIELD OF THE INVENTION

The invention relates to selective Histamine H4 receptor antagonists orinhibitors of Histamine H4 receptor gene expression for the treatmentand/or the prevention of vestibular disorders.

BACKGROUND OF THE INVENTION

Vestibular (inner ear) disorders can cause dizziness, vertigo,imbalance, hearing changes, nausea, fatigue, anxiety, difficultyconcentrating, and other symptoms, with potentially devastating effectson a person's day-to-day functioning, ability to work, relationshipswith family and friends, and quality of life.

Anti-histaminergic compounds are widely used as treatments againstvestibular disorders, like vertigos. Histaminergic agonists andantagonists act on the vestibular system both peripherally andcentrally, and could interfere with the recovery process afterperipheral vestibular lesion (Lacour and Sterkers, 2001). Histaminereceptor family comprises four subtypes: H1 and H2 receptor discoveredin 1966, H3 receptor discovered in 1983 and H4 receptor identified in2000. The H4 receptor was identified on the basis of its homology withthe H3 receptor (31% at protein level and 54% within the transmembranemembrane). Over the four histamine receptors (HR1 to HR4) HR3 appearedto regulate the vestibular inputs (Chavez 2005). In the field of thehistaminergic treatment of vertigo, betahistine (BH) is one of the broadrange of antivertiginous compound. The facilitator action of BH has beendescribed in central vestibular compensation (Lacour and Sterkers, 2001;Tighilet et al. 2005), but its effects on peripheral vestibularreceptors has only been reported in lower vertebrates (Housley et al.1988; Tomoda et al. 1997; Botta et al. 1998; Soto et al. 2001; Chavez etal. 2005). BH has been reported to present a complex function as anagonist of H1 histaminic receptor, and as an antagonist of the H3receptor (Arrang et al. 1985). In the peripheral vestibular receptorsisolated from axolotl, BH inhibits the afferent discharge with an IC50of 800 μM and a maximum effect around 10 mM (Chavez 2005). These studiesconcluded that histamine H3 receptor was the main target of BH (VanCauwenberge and De Moor 1997; Soto 2001; Chavez 2005). A recent studyrealized in cultured rat vestibular neurons, maintained 7 days in vitro,reveals that the application of BH induced a reversible depolarisationof the neuron's membrane and inhibited the evoked discharge withoutaffecting the intrinsic properties of the action potentials.

However, no investigation on Histamine H4 receptor has been made onvestibular disorders.

SUMMARY OF THE INVENTION

The present invention relates to selective Histamine H4 receptorantagonists for the treatment and/or the prevention of vestibulardisorders. The present invention also relates to selective Histamine H4receptor antagonists for use in the treatment and/or the prevention ofvestibular disorders.

The present invention also relates to inhibitors of Histamine H4receptor gene expression for the treatment and/or the prevention ofvestibular disorders.

DETAILED DESCRIPTION OF THE INVENTION

Definitions:

The term “Histamine H4 receptor” has its general meaning in the art. Theterm may include naturally occurring Histamine H4 receptors and variantsand modified forms thereof. The Histamine H4 receptor can be from anysource, but typically is a mammalian (e.g., human and non-human primate)Histamine H4 receptor, particularly a human Histamine H4 receptor.Sequences for Histamine H4 receptor have been published under thereferences NM_021624 (Homo sapiens), NM_153087 (Mus musculus) andNM_131909 (Rattus norvegicus).

An “inhibitor of gene expression” refers to a natural or syntheticcompound that has a biological effect to inhibit or significantly reducethe expression of a gene. Consequently an “inhibitor of Histamine H4receptor gene expression” refers to a natural or synthetic compound thathas a biological effect to inhibit or significantly reduce theexpression of the gene encoding for the Histamine H4 receptor.

By “receptor antagonist” is meant a natural or synthetic compound thathas a biological effect opposite to that of a receptor agonist. The termis used indifferently to denote a “true” antagonist and an inverseagonist of a receptor. A “true” receptor antagonist is a compound whichbinds the receptor and blocks the biological activation of the receptor,and thereby the action of the receptor agonist, for example, bycompeting with the agonist for said receptor. An inverse agonist is acompound which binds to the same receptor as the agonist but exerts theopposite effect. Inverse agonists have the ability to decrease theconstitutive level of receptor activation in the absence of an agonist.

The term “Histamine H4 receptor antagonist” includes any chemical entitythat, upon administration to a patient, results in inhibition ordown-regulation of a biological activity associated with activation ofthe Histamine H4 receptor in the patient, including any of thedownstream biological effects otherwise resulting from the binding toHistamine H4 receptor of its natural ligand. Such Histamine H4 receptorantagonists include any agent that can block Histamine H4 receptoractivation or any of the downstream biological effects of Histamine H4receptor activation. For example, such Histamine H4 receptor antagonistscan act by occupying the ligand binding site or a portion thereof of theHistamine H4 receptor, thereby making the receptor inaccessible to itsnatural ligand so that its normal biological activity is prevented orreduced.

In the context of the present invention, Histamine H4 receptorantagonists are selective for the Histamine H4 receptor as compared withthe other histamine receptors, such as histamine H1 receptor, histamineH2 receptor, and histamine H3 receptor. By “selective” it is meant thatthe affinity of the antagonist for the human Histamine H4 receptor is atleast 10-fold, preferably 25-fold, more preferably 100-fold, stillpreferably 500-fold higher than the affinity for the other humanhistamine receptor (H1, H2 and H3).

The affinity of an antagonist for Histamine H4 receptor may bequantified by measuring the activity of Histamine H4 receptor in thepresence a range of concentrations of said antagonist in order toestablish a dose-response curve. From that dose response curve, an IC₅₀value may be deduced which represents the concentration of antagonistnecessary to inhibit 50% of the response to an agonist in definedconcentration. The IC₅₀ value may be readily determined by the oneskilled in the art by fitting the dose-response plots with adose-response equation as described by De Lean et al. (1979). IC₅₀values can be converted into affinity constant (Ki) using theassumptions of Cheng and Prusoff (1973).

Accordingly, a selective Histamine H4 receptor antagonist is a compoundfor which at least one of the ratios (i) K_(i) H3:K_(i) H4, and (ii)IC₅₀ H3: IC₅₀ H4, is above 10:1, preferably 25:1, more preferably 100:1,still preferably 1000:1.

The antagonistic activity of compounds towards the Histamine H4receptors may be determined using various methods, such as thosedescribed in Thurmond R L et al. (2004) or Venable J D. et al. (2005).

The term “small organic molecule” refers to a molecule of a sizecomparable to those organic molecules generally used in pharmaceuticals.The term excludes biological macromolecules (e. g., proteins, nucleicacids, etc.). Preferred small organic molecules range in size up toabout 5000 Da, more preferably up to 2000 Da, and most preferably up toabout 1000 Da.

As used herein, the term “subject” denotes a mammal, such as a rodent, afeline, a canine, and a primate. Preferably, a subject according to theinvention is a human.

The term “vestibular disorders” refers to conditions characterized bydizziness, visual or gaze disturbances and balance impairment.Vestibular disorders could result from diverse damages or dysfunction ofthe inner ear, among them the acute and chronic syndromes. Examples ofvestibular disorders that are contemplated by the invention include butare not limited to vertigo, benign paroxysmal vertigo, vestibularneuritis, spell of Ménière's disease, endolymphatic hydrops,perilymphatic fistula, head trauma with vestibular disorders,labyrinthine haemorrhage, chronic or acute labyrinthine infection,serous labyrinthine, barotraumatism, autoimmune inner ear disease,migraine with vestibular syndromes, vestibular syndromes afterchirurgical treatments of middle ear, middle ear, endolymphatic sac orpontocerebellar angle, inner ear channelopathies, chronic Menièredisease, vestibular, schwannomas, presbyvestibulia, familial episodicvertigo and ataxia.

In its broadest meaning, the term “treating” or “treatment” refers toreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition.

In particular, “prevention” of vestibular disorders may refer to theadministration of the compounds of the present invention prevent thesymptoms of vestibular disorders.

“Pharmaceutically” or “pharmaceutically acceptable” refers to molecularentities and compositions that do not produce an adverse, allergic orother untoward reaction when administered to a mammal, especially ahuman, as appropriate. A pharmaceutically acceptable carrier orexcipient refers to a non-toxic solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.

Therapeutic Methods and Uses

The present invention provides methods and compositions (such aspharmaceutical compositions) for treating vestibular disorders or foruse in treating vestibular disorders.

According to a first aspect, the invention relates to selectiveHistamine H4 receptor antagonists for treating vestibular disorders orfor use in treating vestibular disorders.

In one embodiment, the selective Histamine H4 receptor antagonists maybe low molecular weight antagonists, e. g. a small organic molecule.

According to one embodiment of the invention, a selective H4 receptorantagonist refers to a molecule that has an affinity for H4 receptor atleast 10 fold, preferably 25 fold, preferably 50 fold, more preferably100 fold, and even more preferably 500 fold higher than its affinity forany one of H1, H2 or H3 receptor.

According to another embodiment of the invention, a selective H4receptor antagonist is a molecule for which one of the ratios Ki H3:KiH4 and (ii) IC50 H3 : IC50 H4 is above 10:1, preferably 25:1, preferably50:1, more preferably 100:1 and even more preferably between 500:1 to1000:1.

The affinity for H4 receptor and others (H1, H2 and H3) receptors may becharacterized by any conventional technique known in the art. Forexample, it can be determined by binding assays. Said assays use cellspellets from cells such as SK-N-MC or HEK293 T, cells transfected withhuman, rat or mouse H4, H3, H2 or H1 receptor (Lovenberg et al. 1999,Liu et al. 2001a,b, Thurmond et al. 2004). Cells can be homogenized in50 mM Tris pH 7.5 containing 5 mM EDTA, and supernantants from an 800 gspin are collected and recentrifuged at 30 000 g for 30 min. Pellets arethen homogenized in 50 mM Tris pH 7.5 containing 5 mM EDTA. For H4competition binding studies, human, mouse or rat cells are incubatedusing different concentrations of [³H] histamine (specific for eachspecies, for example 10, 40 and 50 nM respectively), in the presence orabsence of the molecule to be tested, for about 45 min at 25° C. Thenon-specific binding is defined using 100 μM unlabeled histamine orusing 10⁻⁶ M of specific or selective H4 receptor antagonist such asJNJ-7777120 or JNJ-10191584. The Kd values for the human, mouse and ratH4 receptor were determined with this method to be 5, 42 and 178 nMrespectively, and the Bmax values were determined to be 1.12, 1.7 and0.68 pmol/mg protein, respectively. Similarly, the ligand used for theH3 receptor binding assays is for example [³H]N-a-methyl histamine, andthe non-specific binding is defined using 100 μM unlabeled histamine.The Kd value for human H3 receptor was determined with this method to be1 nM and the Bmax value 2.13 pmol/mg protein. The ligand used for the H1receptor binding was [³H]pyrilamine and the non-specific activity isdefined using 10 μM unlabeled diphenhydramine. The Kd value for human H1receptor was determined with this method to be 1 nM and the Bmax value2.68 pmol/mg protein. In these assays, the cells are typically incubatedwith different concentration of such as 10⁻¹¹ to 10⁻⁴ M of molecule tobe tested.

The person skilled in the art willing to verify or determine theantagonist activity of the molecule to be tested may use any methodknown in the art and for example a cell-based cAMP assay. Said assay useSK-n-MC cell lines transfected with H4, H3, H2 or H1 receptor and areporter gene construct such as b-galactosidase under the control ofcyclic AMP-responsive elements. Cells are plated overnight before theassay. Histamine is used as the agonist molecule. For determination ofantagonist activity, molecules to be tested are added 10 min prior tothe addition of agonist. Forskolin (5 μM final concentration) is added10 min after the addition of histamine. Cells are then maintained at 37°C. for 6 hours, and then after washing lysed with about 25 μl of 0.1×assay buffer (10 mM sodium phosphate, pH 8, 0.2 mM MgSO₄ and 0.01 mMMnCl₂) and incubated at room temperature for 10 min. Cells are thenincubated for 10 min with about 100 μl of 1× assay buffer containing0.5% (v/v) Trition X-100 and 40 mM β-mercaptoethanol. Color can bedeveloped using 25 μl of 1 mg/ml substrate solution such as chlorophenolred b-D-galactopyranoside, and quantified by measuring the absorbance at570 nm. The data obtained for each concentration-response curve can befitted to a sigmoidal curve to obtain the maximum response, Hillcoefficient and EC₅₀.

Exemplary selective Histamine H4 antagonists that are contemplated bythe invention include but are not limited to those described in U.S.Pat. No. 6,803,362; US Patent Application Publication Nos. 2004/0105856,2004/0127395, 2004/0132715, 2004/0048878, 2004/0058934, 2005/0070527,2005/0070550, 2005/0261309, 2007/0238771, 2008/0269239, 2008/0261946,2008/0188452, 2009/275748, and International Patent Application NosWO2005/054239, WO2005/014556, WO2007/031529, WO2007/072163,WO2007/090852, WO2007/117399, WO2007/120690, WO2008/074445,WO2008/008359, WO2008/031556, WO2008/100565, WO2008/003702,WO2009/134726, WO2009/115496, WO2009/114575, WO2009/080721,WO2009/077608, WO2009/071625, WO2009/068512, WO2009/056551,WO2009/038673, WO2009/077608, WO2009/079001 and WO2009/047255, which areincorporated herein by reference.

Other exemplary selective Histamine H4 antagonists that are contemplatedby the invention include but are not limited to those described inJablonowski J A et al. (2003), Venable J D. et al. (2005), Thurmond R L.et al. (2004), Herman D. et al. (2005) Robin L. et al. (2004), Cowart MD. et al. (2008) and Liu H. et al. (2008).

Typically, compounds that may be contemplated by the invention are2-aminopyrimidine derivatives, such as described in WO2005/054239 orWO2005/014556, or quinazoline derivatives such as described inWO2008/003702.

In one embodiment of the invention, the selective H4 antagonist isselected among bicyclic heteroaryl-substituted imidazole compounds, suchas the ones described in WO2009/079001 and WO2007/120690; thieno- andfuro-pyrimidine compounds such as the ones described in WO2009/038673;2-Aminopyrimidine compounds such as the ones described in WO2008/100565,WO2009077608, WO2009/068512, WO2005/054239, WO2008/031556, WO2008122378and WO2005/014556; benzofuro- and benzothienopyrimidine compounds suchas the ones described in WO2008/008359; Furo[3,2-d]pyrimidinederivatives such as the ones described in WO2009/056551 andWO2009/115496; 4-Amino-pyrimidine derivatives such as the ones describedin WO2009/080721; amino pyrimidine compounds such as the ones describedin WO2007/090852; enantiomers of amino pyrimidine compounds such as theones described in WO2007/090853; azetidine amino pyrimidine compounds,such, as the ones described in WO2007/090854; pyrimidine compounds suchas the ones described in WO2007/039467, WO2006/050965 and WO2007/072163;mequitazine, such as the ones described in WO2009/071625; substitutedpyrimidine derivatives, particularly macrocyclic fused substitutedpyrimidine derivatives, such as the ones described in WO2009/134726;macrocyclic spiro pyrimidine compounds, particularly tricyclic spiropyrimidine compounds, such as the ones described in WO2009/114575;macrocyclic benzofused pyrimidine compounds, such as the ones describedin WO2008/060767; heteroaryl-fused macrocylciv pyrimidine derivatives,particularly heteroaryl-fused macrocyclic 2,4-diaminopyrimidinecompounds, such as the ones described in WO2009137492;5,6,7,8-tetrahydroquinazolin-2-amine derivatives, such as the onesdescribed in WO2009123967; octahydropyrrolo[3,4-c]pyrrole derivatives,such as the ones described in WO2006056848; tricyclic andheterotricyclic derivatives, such as the ones described inWO2008/074445; heterobicyclic compounds such as the ones described inWO2009047255; quinazolines and related heterocyclic compounds, such asthe ones described in WO2008/003702; imidazole derivatives ofpiperidine, such as the ones described in WO2005/014579; bicyclicpyrimidine compound, such as the ones described in WO2009107767 (allreferences being incorporated by reference).

In a particular embodiment, the selective Histamine H4 antagonists areselected from those described in the international Patent ApplicationWO2007/120690:(1H-Benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(1H-Benzoimidazol-2-yl)-(4-ethyl-piperazin-1-yl)-methanone;(1H-Benzoimidazol-2-yl)-(3-methyl-piperazin-1-yl)-methanone;(1H-Benzoimidazol-2-yl)-(4-methyl-[1,4]diazepan-1-yl)-methanone;1H-Benzoimidazole-2-carboxylic acid(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amide;(5-Chloro-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5-Chloro-1H-benzoimidazol-2-yl)-piperazin-1-yl-methanone;(5-Chloro-1H-benzoimidazol-2-yl)-(3-methyl-piperazin-1-yl)-methanone;(5,6-Difluoro-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5,6-Difluoro-1H-benzoimidazol-2-yl)-(4-ethyl-piperazin-1-yl)-methanone;(5,6-Difluoro-1H-benzoimidazol-2-yl)-(3-methyl-piperazin-1-yl)-methanone;(5,6-Difluoro-1H-benzoimidazol-2-yl)-(4-methyl-[1,4]diazepan-1-yl)-methanone;5,6-Difluoro-1H-benzoimidazole-2-carboxylic acid(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amide;(6-Chloro-5-fluoro-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(6-Chloro-5-fluoro-1H-benzoimidazol-2-yl)-(4-methyl-[1,4]diazepan-1-yl)-methanone;6-Chloro-5-fluoro-1H-benzoimidazole-2-carboxylic acid(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amide;(5-Chloro-6-methyl-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5-Chloro-6-methyl-1H-benzoimidazol-2-yl)-piperazin-1-yl-methanone;(4-Methyl-1H-benzoimidazol-2-yl)-(3-methyl-piperazin-1-yl)-methanone;(4-Ethyl-piperazin-1-yl)-(4-methyl-1H-benzoimidazol-2-yl)-methanone;(4-Methyl-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(4-Methyl-1H-benzoimidazol-2-yl)-piperazin-1-yl-methanone;4-Methyl-1H-benzoimidazole-2-carboxylic acid(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amide;5-Methyl-1H-benzoimidazole-2-carboxylic acid(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amide;(5-Methyl-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(4-Methyl-piperazin-1-yl)-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-methanone;Piperazin-1-yl-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-methanone;(5-Fluoro-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(4-Ethyl-piperazin-1-yl)-(5-fluoro-1H-benzoimidazol-2-yl)-methanone;(5-Fluoro-1H-benzoimidazol-2-yl)-piperazin-1-yl-methanone;(5-Fluoro-1H-benzoimidazol-2-yl)-(3-methyl-piperazin-1-yl)-methanone;5-Fluoro-1H-benzoimidazole-carboxylic acid(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amide;Benzooxazol-2-yl-(4-methyl-piperazin-1-yl)-methanone;(7-Methyl-benzooxazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5-Methyl-benzooxazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(4-Methyl-benzooxazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;Benzothiazol-2-yl-(4-methyl-piperazin-1-yl)-methanone;(5-Benzoyl-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(4-Chloro-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(4-Methyl-piperazin-1-yl)-(4-nitro-1H-benzoimidazol-2-yl)-methanone;(4-Amino-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(4-Isopropylamino-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;C-(5-Chloro-1H-benzoimidazol-2-yl)-C-(4-methyl-piperazin-1-yl)-methyleneamine;(4,6-Difluoro-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(4-Methyl-piperazin-1-yl)-(5-nitro-1H-benzoimidazol-2-yl)-methanone;(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5-Bromo-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5,6-Dichloro-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(4,5-Dimethyl-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5,6-Dimethyl-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5-Methoxy-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5-Chloro-benzooxazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5-Fluoro-benzooxazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(6-Fluoro-benzooxazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5,7-Difluoro-benzooxazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(4-Methyl-piperazin-1-yl)-(5-trifluoromethoxy-benzooxazol-2-yl)-methanone;(5-Chloro-benzothiazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(4-Methyl-piperazin-1-yl)-(5-trifluoromethyl-benzothiazol-2-yl)-methanone;(4-Methyl-piperazin-1-yl)-(6H-thieno[2,3-b]pyrrol-5-yl)-methanone;(Hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-(6H-thieno[2,3-b]pyrrol-5-yl)-methanone;(2-Chloro-6H-thieno[2,3-b]pyrrol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;(2-Chloro-6H-thieno[2,3-b]pyrrol-5-yl)-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-methanone;(2-Chloro-6H-thieno[2,3-b]pyrrol-5-yl)-piperazin-1-yl-methanone;(4H-Furo[3,2-b]pyrrol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;(4-Methyl-piperazin-1-yl)-(4H-thieno[3,2-b]pyrrol-5-yl)-methanone;Piperazin-1-yl-(4H-thieno[3,2-b]pyrrol-5-yl)-methanone;(3-Methyl-piperazin-1-yl)-(4H-thieno[3,2-b]pyrrol-5-yl)-methanone;(2-Chloro-4H-thieno[3,2-b]pyrrol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;(2-Chloro-4H-thieno[3,2-b]pyrrol-5-yl)-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-methanone;(3-Bromo-4H-thieno[3,2-b]pyrrol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;4-Methyl-piperazin-1-yl)-(3-methyl-4H-thieno[3,2-b]pyrrol-5-yl)-methanone;(2-Methyl-4H-furo[3,2-b]pyrrol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;(2,3-Dimethyl-4H-furo[3,2-b]pyrrol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;(2.3-Dimethyl-4H-thieno[3,2-b]pyrrol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;(2,3-Dichloro-6H-thieno[2,3-b]pyrrol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;(2-Methyl-4H-furo[3,2-b]pyrrol-5-yl)-piperazin-1-yl-methanone;(3-Bromo-4H-thieno[3,2-b]pyrrol-5-yl)-piperazin-1-yl-methanone;(3-Bromo-4H-thieno[3,2-b]pyranyl-5-yl)-(3-methyl-piperazin-1-yl)-methanone;(3-Methyl-4H-thieno[3,2-b]pyrrol-5-yl)-piperazin-1-yl-methanone;(3-Methyl-piperazin-1-yl)-(3-methyl-4H-thieno[3,2-b]pyrrol-5-yl)-methanone;(2-Chloro-3-methyl-4H-thieno[3,2-b]pyrrol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;(2-Chloro-3-methyl-4H-thieno[3,2-b]pyrrol-5-yl)-piperazin-1-yl-methanone;(2,3-Dichloro-4H-thieno[3,2-1b]pyrrol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;(2,3-Dimethyl-6H-thieno[2,3-b]pyrrol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;(2-Chloro-3-methyl-6H-thieno[2,3-b]pyrrol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;(3-Chloro-2-methyl-6H-thieno[2,3-b]pyrrol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;(2-Bromo-6H-thieno[2,3-b]pyranol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;(3-Bromo-6H-thieno[2,3-b]pyrrol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;(4-Methyl-piperazin-1-yl)-(2-phenyl-6H-thieno[2,3-b]pyrrol-5-yl)-methanone;[2-(4-Chloro-phenyl)-6H-thieno[2,3-b]pyrrol-5-yl]-(4-methyl-piperazin-1-yl)-methanone;(3-Bromo-4H-thieno[3,2-b]pyranol-5-yl)-(3,4-dimethyl-piperazin-1-yl)-methanone;(3,4-Dimethyl-piperazin-1-yl)-(3-methyl-4H-thieno[3,2-b]pyrrol-5-yl)-methanone;(2-Bromo-3-methyl-4H-thieno[3,2-b]pyrrol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;(3-Bromo-2-chloro-4H-thieno[3,2-b]pyrrol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;(2,3-Dichloro-4H-thieno[3,2-b]pyrrol-5-yl)-(3-methyl-piperazin-1-yl)-methanone;(4-Methyl-piperazin-1-yl)-(2-phenyl-4H-thieno[3,2-b]pyrrol-5-yl)-methanone;(4-Methyl-piperazin-1-yl)-[2-(4-trifluoromethyl-phenyl)-4H-thieno[3,2-pyrrol-5-yl]-methanone;8-Methyl-3-(4-methyl-piperazin-1-yl)-1H-quinoxalin-2-one;8-Methyl-3-piperazin-1-yl-1H-quinoxalin-2-one;8-Nitro-3-piperazin-1-yl-1H-quinoxalin-2-one;7,8-Difluoro-3-piperazin-1-yl-1H-quinoxalin-2-one;8-Methyl-3-(3-methyl-piperazin-1-yl)-1H-quinoxalin-2-one;3-(3-Methyl-piperazin-1-yl)-1H-quinoxalin-2-one;3-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-8-methyl-1H-quinoxalin-2-one;6-Chloro-3-(4-methyl-piperazin-1-yl)-1H-quinoxalin-2-one;7-Chloro-3-(4-methyl-piperazin-1-yl)-1H-quinoxalin-2-one;3-(4-Methyl-piperazin-1-yl)-6-trifluoromethyl-1H-quinoxalin-2-one;3-(4-Methyl-piperazin-1-yl)-7-trifluoromethyl-1H-quinoxalin-2-one;6,7-Dichloro-3-(4-methyl-piperazin-1-yl)-1H-quinoxalin-2-one;6,7-Dichloro-3-piperazin-1-yl-1H-quinoxalin-2-one;6,7-Dichloro-3-(4-methyl-[1,4]diazepan-1-yl)-1H-quinoxalin-2-one;6,7-Difluoro-3-(4-methyl-piperazin-1-yl)-1H-quinoxalin-2-one;7-Chloro-6-methyl-3-(4-methyl-piperazin-1-yl)-1H-quinoxalin-2-one;6-Chloro-7-methyl-3-(4-methyl-piperazin-1-yl)-1H-quinoxalin-2-one;6-Fluoro-3-(4-methyl-piperazin-1-yl)-1H-quinoxalin-2-one;7,8-Difluoro-3-(4-methyl-piperazin-1-yl)-1H-quinoxalin-2-one;8-Chloro-3-(4-methyl-piperazin-1-yl)-6-trifluoromethyl-1H-quinoxalin-2-one;3-Piperazin-1-yl-6-trifluoromethyl-1H-quinoxalin-2-one;3-Piperazin-1-yl-7-trifluoromethyl-1H-quinoxalin-2-one;6-Chloro-7-fluoro-3-(4-methyl-piperazin-1-yl)-1H-quinoxalin-2-one;7-Chloro-6-fluoro-3-(4-methyl-piperazin-1-yl)-1H-quinoxalin-2-one;7-Chloro-3-piperazin-1-yl-1H-quinoxalin-2-one;6-Chloro-3-piperazin-1-yl-1H-quinoxalin-2-one;6-Chloro-3-(3-methyl-piperazin-1-yl)-1H-quinoxalin-2-one;7-Chloro-3-(3-methyl-piperazin-1-yl)-1H-quinoxalin-2-one;3-(3-Methyl-piperazin-1-yl)-6-trifluoromethyl-1H-quinoxalin-2-one;3-(3-Methyl-piperazin-1-yl)-7-trifluoromethyl-1H-quinoxalin-2-one;2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4,5-dimethyl-1H-benzoimidazole;2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole;2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluoromethoxy-1H-benzoimidazole;5-tert-Butyl-2-{3-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;5-tert-Butyl-2-{3-chloro-4-[3-(4-methyl-piperazin-1yl)-propoxy]-phenyl}-1H-benzoimidazole;4,5-Dimethyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;5-tert-Butyl-2-{3-[4-(4-methyl-piperazin-1yl)-butoxy]-phenyl}-1H-benzoimidazole;5-tert-Butyl-2-{3-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-phenyl}-1H-benzoimidazole;(1-{3-[4-(5-tert-Butyl-1H-benzoimidazol-2-yl)-2-chloro-phenoxy]-propyl}-pyrrolidin-3-yl)-dimethylamine;2-{3-Fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole;5-Methyl-2-{4-[3-(4-methyl-piperazin-1-yl)-propoxy]-naphthalen-1-yl}-1H-benzoimidazole;4-[3-(5-tert-Butyl-1H-benzoimidazol-2-yl)-phenoxy]-1-(4-methyl-piperazin-1-yl)-butan-1-one;5-Chloro-2-[3-chloro-4-(3-piperazin-1-yl-propoxy)-phenyl]-6-fluoro-1H-benzoimidazole;5-tert-Butyl-2-{3-methyl-4-[4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4,6-dimethyl-1H-benzoimidazole;2-{2-Chloro-4-[2-methyl-3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole;5-Chloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-6-methyl-1H-benzoimidazole;6-Chloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-ethyl-1H-benzoimidazole;5-tert-Butyl-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;5-Chloro-2-{3-fluoro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;2-{2-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4,6-dimethyl-1H-benzoimidazole;5-Chloro-6-methyl-2-{3-[4-(4-methyl-piperazin-1-yl)-butoxy]-phenyl}-1H-benzoimidazole;2-{3-Fluoro-4-[4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methyl-1H-benzoimidazole;5,6-Difluoro-2-{3-fluoro-4-[4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;2-{3-Fluoro-4-[4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;2-{2-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4,5-dimethyl-1H-benzoimidazole;5,6-Dimethyl-2-{3-[4-4-(4-methyl-piperazin-1-yl)-butoxy]-phenyl}-1H-benzoimidazole;2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4,6-dimethyl-1H-benzoimidazole;2-{2-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole;5-tert-Butyl-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;2-{3-Methoxy-4-[3-(4-methyl-piperazin-1-yl)-propoxy3-phenyl}-5-trifluoromethyl-1H-benzoimidazole;5-Chloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-6-fluoro-1H-benzoimidazole;5,6-Dichloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;5-Chloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;5-Chloro-2-{2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-6-fluoro-1H-benzoimidazole;5-Chloro-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methyl-1H-benzoimidazole;5,6-Dichloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;5-Chloro-6-methyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methyl-1H-benzoimidazole;5-Chloro-2-{3-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluoromethyl-1H-benzoimidazole;5-Chloro-6-fluoro-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;5-Methyl-2-{3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;2-{3-Methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;5-Chloro-6-fluoro-2-{3-methoxy-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;2-{3-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-methoxy-1H-benzoimidazole;5-tert-Butyl-2-{3,5-dibromo-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;2-{2-Methoxy-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluoromethyl-1H-benzoimidazole;2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-trifluoromethyl-1H-benzoimidazole;2-{3-[3-(4-Methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;(2-{3-[4-(4-Methyl-piperazin-1-yl)-butoxy]-phenyl}-1H-benzoimidazol-5-yl)-phenyl-methanone;6-Chloro-2-{2-chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole;5-tert-Butyl-2-{3-chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4,5-dimethyl-1H-benzoimidazole;5-Chloro-6-methyl-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;5-Chloro-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;5-Chloro-6-fluoro-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;5-tert-Butyl-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;5-Methyl-2-{4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;2-{4-[3-(1-Methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;6-Chloro-2-{2-fluoro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole;5-Fluoro-2-{2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;4-Chloro-2-{2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;6-Chloro-4-methyl-2-{2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-3H-naphtho[1,2-d]imidazole;4,6-Dimethyl-2-{2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole;2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-fluoro-4-methyl-1H-benzoimidazole;2-{2-Chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-3H-naphtho[1,2-d]imidazole;6-Chloro-2-{2-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole;2-{3-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4-methyl-1H-benzoimidazole;4,6-Dimethyl-2-{3-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-phenyl}-1H-benzoimidazole;5-Chloro-2-{4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;2-{4-[3-(4-Methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;{2-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzyl}-dimethyl-amine;{2-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzyl}-dimethyl-amine;4-{3-[4-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-propyl}-[1,4]diazepan-5-one;4-{3-[4-(5-tert-Butyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-propyl}-1-methyl-[1,4]diazepan-5-one;5-tert-Butyl-2-{2-methyl-4-[3-(2-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;5-tert-Butyl-2-{2-methyl-4-[3-(2-methyl-piperazin-1-yl)-propoxy]-phenyl}-1H-benzoimidazole;6-Chloro-4-methyl-2-[2-methyl-4-(3-piperidin-4-yl-propoxy)-phenyl]-1H-benzoimidazole;5-Fluoro-4-methyl-2-[2-methyl-4-(3-piperidin-4-yl-propoxy)-phenyl]-1H-benzoimidazole;6-Chloro-2-{4-[3-(1-ethyl-piperidin-4-yl)-propoxy]-2-methyl-phenyl}-4-methyl-1H-benzoimidazole;{2-[3-Chloro-4-(4-methyl-1H-benzoimidazol-2-yl)-phenoxy]-ethyl}-methyl-(1-methyl-piperidin-4-yl)-amine;6-Chloro-4-methyl-2-{2-methyl-4-[2-(1-methyl-piperidin-4-yloxy)-ethoxy]-phenyl}-1H-benzoimidazole;6-Chloro-4-methyl-2-{2-methyl-4-[3-(1-methyl-1,2-6-tetrahydro-pyridin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;5-Fluoro-4-methyl-2-{2-methyl-4-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-phenyl}-1H-benzoimidazole;6-Fluoro-7-methyl-2-{3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole;7-Methyl-2-{3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole;6,7-Dimethyl-2-{3-[4-1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole;(5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5-Fluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(1H-Indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5-Benzyloxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5-Methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5,6-Dimethoxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(4-Methyl-piperazin-1-yl)-(7-nitro-1H-indol-2-yl)-methanone;(4-Methyl-piperazin-1-yl)-(5-nitro-3-phenyl-1H-indol-2-yl)-methanone;(4-Methyl-piperazin-1-yl)-(5-trifluoromethoxy-1H-indol-2-yl)-methanone;(6-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5,7-Difluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(6-Fluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(4,6-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(1H-Indol-2-yl)-(4-octyl-piperazin-1-yl)-methanone;(4-Ethyl-piperazin-1-yl)-(1H-indol-2-yl)-methanone;(1H-Indol-2-yl)-(4-isopropyl-piperazin-1-yl)-methanone;[4-(3-Dimethylamino-propyl)-piperazin-1-yl]-(1H-indol-2-yl)-methanone;(4-Butyl-piperazin-1-yl)-(1H-indol-2-yl)-methanone;(4-Cyclopentyl-piperazin-1-yl)-(1H-indol-2-yl)-methanone;(1H-Indol-2-yl)-(4-phenethyl-piperazin-1-yl)-methanone;(1H-Indol-2-yl)-[4-(2-piperidin-1-yl-ethyl)-piperazin-1-yl]-methanone;[4-(2-Ethoxy-ethyl)-piperazin-1-yl]-(1H-indol-2-yl)-methanone;(4-sec-Butyl-piperazin-1-yl)-(1H-indol-2-yl)-methanone;[4-(1-Ethyl-propyl)-piperazin-1-yl]-(1H-indol-2-yl)-methanone;(1H-Indol-2-yl)-[4-(3-phenyl-propyl)-piperazin-1-yl]-methanone;(1H-Indol-2-yl)-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-methanone;[4-(2-Dipropylamino-ethyl)-piperazin-1-yl]-1H-indol-2-yl)-methanone;(1H-Indol-2-yl)-[4-(3-phenyl-allyl)-piperazin-1-yl]-methanone;(1H-Indol-2-yl)-(4-pentyl-piperazin-1-yl)-methanone;(4-Heptyl-piperazin-1-yl)-(1H-indol-2-yl)-methanone;[4-(2-Diethylamino-ethyl)-piperazin-1-yl]-(1H-indol-2-yl)-methanone;(1H-Indol-2-yl)-[4-(4-methoxy-butyl)-pyperazin-1-yl]-methanone;5-Chloro-7-methyl-2-{3-[4-1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole;5,7-Dimethyl-2-{2-methyl-3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole;5-Chloro-7-methyl-2-{2-methyl-3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole;6-Fluoro-7-methyl-2-{2-methyl-3-[4-(1-methyl-piperidin-4-yl)-butoxy]-phenyl}-1H-benzoimidazole;6-Fluoro-7-methyl-2-{3-[3-(1-methyl-piperidin-4-yloxy)-propoxy]-phenyl}-1H-benzoimidazole;{2-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-methanol;6-Chloro-4-methyl-2-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;4-Methyl-2-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;5-Fluoro-4-methyl-2-{6-[3-(4-methyl-piperaztn-1-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;4-Methyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;4,5-Dimethyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;4-Chloro-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;5-Fluoro-4-methyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;4,5-Dimethyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;4,6-Dimethyl-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;4-Chloro-2-{4-methyl-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;2-{4-Chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-5-fluoro-4-methyl-1H-benzoimidazole;2-{4-Chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-4-methyl-1H-benzoimidazole;6-Chloro-2-{4-chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-4-methyl-1H-benzoimidazole;2-{4-Chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-4,6-dimethyl-1H-benzoimidazole;2-{4-Methoxy-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-4-methyl-1H-benzoimidazole;5-Fluoro-2-{4-methoxy-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridin-3-yl}-4-methyl-1H-benzoimidazole;5-Fluoro-4-methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;4-Methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;6-Chloro-4-methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;4,5-Dimethyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;4,6-Dimethyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;5-Chloro-4-methyl-2-{6-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-propoxy]-pyridin-3-yl}-1H-benzoimidazole;5-Fluoro-4-methyl-2-{6-[3-(1-methyl-piperidin-4-yl)-propoxy]-4-pyrrolidin-1-ylmethyl-pyridin-3-yl}-1H-benzoimidazole;2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-methyl-1H-benzoimidazole;2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-fluoro-4-methyl-1H-benzoimidazole;2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-6-chloro-4-methyl-1H-benzoimidazole;2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,6-dimethyl-1H-benzoimidazole;2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dimethyl-1H-benzoimidazole;2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-chloro-4-methyl-1H-benzoimidazole;2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-tert-butyl-1H-benzoimidazole;5-tert-Butyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;2-{5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-fluoro-4-methyl-1H-benzoimidazole;2-{5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dimethyl-1H-benzoimidazole;4,6-Dimethyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;4-Methyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;4,5-Dimethyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;5-Fluoro-4-methyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;6-Chloro-4-methyl-2-{2-[4-(4-methyl-piperazin-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;5-Fluoro-4-methyl-2-{2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;4,5-Dimethyl-2-{2-[4-(4-methyl-[1,4]diazepan-1-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;4,6-Dimethyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;4-Methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;5-Fluoro-4-methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;4-Chloro-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;4,5-Dimethyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;6-Chloro-4-methyl-2-{2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;5-tert-Butyl-2-[2-(4-piperidin-4-yl-butoxy)-pyridin-4-yl]-1H-benzoimidazole;4,6-Dimethyl-2-[2-(4-piperidin-4-yl-butoxy)-pyridin-4-yl]-1H-benzoimidazole;2-{2-[4-(1-Ethyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dimethyl-1H-benzoimidazole;4,6-Dimethyl-2-{3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;4-Methyl-2-{3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;6-Chloro-4-methyl-2-{3-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-methyl-1H-benzoimidazole;2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,5-dimethyl-1H-benzoimidazole;4-Chloro-2-{3-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-fluoro-4-methyl-1H-benzoimidazole;2-{3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,6-dimethyl-1H-benzoimidazole;6-Chloro-2-{3-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-methyl-1H-benzoimidazole;5-Fluoro-4-methyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;5-Chloro-6-fluoro-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;5-tert-Butyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;4,5-Dimethyl-2-{5-methyl-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;2-{5-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4,6-dimethyl-1H-benzoimidazole;5-tert-Butyl-2-{5-chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-1H-benzoimidazole;2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-4-chloro-1H-benzoimidazole;2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-chloro-6-fluoro-1H-benzoimidazole;2-{5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridin-4-yl}-5-chloro-1H-benzoimidazole;1-(3-{4-[4,5-Bis-(4-bromo-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-4-methyl-piperazine;1-{3-[3-Chloro-4-(4,5-diphenyl-1H-imidazol-2-yl)-phenoxy]-propyl}-4-methyl-piperazine;1-(3-{4-[4,5-Bis-(4-methoxy-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-4-methyl-piperazine;1-{3-[3-Chloro-4-(4,5-di-p-tolyl-1H-imidazol-2-yl)-phenoxy]-propyl}-4-methyl-piperazine;1-(3-{4-[4,5-Bis-(3-methoxy-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-4-methyl-piperazine;1-(3-{4-[4,5-Bis-(3-methoxy-phenyl)-1H-imidazol-2-yl]-2-fluoro-phenoxy}-propyl)-4-methyl-piperazine;1-(3-{4-[4,5-Bis-(4-bromo-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-4-methyl-[1,4]diazepane;1-(3-{4-[4,5-Bis-(3-methoxy-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-4-methyl-[1,4]diazepane;2-{3-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4,5,6,7-tetrahydro-1H-benzoimidazole;2-{2-Chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-phenyl}-4,5,6,7-tetrahydro-1H-benzoimidazole;1-Methyl-4-{3-[3-methyl-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-piperidine;4-{3-[3-Chloro-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-1-methyl-piperidine;4-(3-{3-Chloro-4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-phenoxy}-propyl)-1-methyl-piperidine;4-(3-{3-Chloro-4-[4-(3,5-dichloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxy}-propyl)-1-methyl-piperidine;4-(3-{4-[4-(3,5-Dichloro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-methyl-phenoxy}-propyl)-1-methyl-piperidine;4-(3-{3-Chloro-4-[4-(4-chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxy}-propyl)-1-methyl-piperidine;4-(3-{4-[4,5-Bis-(4-fluoro-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-1-methyl-piperidine;4-(3-{4-[4,5-Bis-(3-methoxy-phenyl)-1H-imidazol-2-yl]-3-chloro-phenoxy}-propyl)-1-methyl-piperidine;4-(3-{3-Chloro-4-[4-(4-chloro-phenyl)-5-p-tolyl-1H-imidazol-2-yl]-phenoxy}-propyl)-1-methyl-piperidine;2-{2-Chloro-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-4,5,6,7-tetrahydro-1H-benzoimidazole;4-{3-[3-Chloro-4-(4-methyl-5-propyl-1H-imidazol-2-yl)-phenoxy]-propyl}-1-methyl-piperidine;4-{3-[3-Chloro-4-(5-ethyl-4-methyl-1H-imidazol-2-yl)-phenoxy]-propyl}-1-methylpiperidine;1-Methyl-4-(2-{3-methyl-4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-phenoxyl}-ethoxy)-piperidine;5-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-pyridine;2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-5-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridine;2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-5-[5-methyl-4-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridine;2-[3-(1-Methyl-piperidin-4-yl)-propoxy]-5-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-pyridine;1-Methyl-4-(3-{5-[5-methyl-4-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridin-2-yloxyl}-propyl)-piperazine;1-Methyl-4-(3-{5-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridin-2-yloxyl}-propyl)-piperazine;4-(4-{3-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxy}-butyl)-1-methyl-piperidine;1-Methyl-4-{4-[3-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-butyl}-piperidine;2-[4-(1-Methyl-piperidin-4-yl)-butoxy]-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-pyridine;2-[4-(1-Methyl-piperidin-4-yl)-butoxy]-4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridine;4-{3-[4-5-Isobutyl-4-methyl-1H-imidazol-2-yl)-3-methyl-phenoxy]-propyl}-1-methyl-piperidine;4-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine;4-{3-[3-Chloro-4-(5-isobutyl-4-methyl-1H-imidazol-2-yl)-phenoxy]-propyl}-1-methyl-piperidine;1-Methyl-4-(4-{3-[5-methyl-4-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-phenoxyl-butyl)-piperidine;1-{3-[2-Chloro-4-(1H-imidazol-2-yl)-phenoxy]-propyl}-4-methyl-piperazine;1-{3-[3-Chloro-4-(4,5-dimethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-4-methyl-piperazine;1-{3-[3-Chloro-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-4-methyl-piperazine;1-{3-[2-Chloro-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-4-methyl-[1,4]diazepane;1-Methyl-4-(3-{3-methyl-4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-phenoxy}-propyl)-piperidine;4-(3-{4-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-methyl-phenoxy}-propyl)-1-methyl-piperidine;4-(2-{4-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-methyl-phenoxy}-ethoxy)-1-methyl-piperidine;1-(3-{4-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-methyl-phenoxy}-2-methyl-propyl)-4-methyl-piperazine;2-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-6-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine;4-Methyl-2-[3-(1-methyl-piperidin-4-yl)-propoxy]-5-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridine;5-Bromo-4-[4-(4-chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine;2,4-Dimethyl-1-{3-[4-4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-phenoxy]-propyl}-piperazine;1,2-Dimethyl-4-{3-[4-(4-phenyl-5-trifluoromethyt-1H-imidazol-2-yl)-phenoxy]-propyl}-piperazine;3-Chloro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-4-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-pyridine;1-Methyl-4-(4-{4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridin-2-yloxyl}-butyl)-[1,4]diazepane;5-Bromo-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-4-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridine;4-[4-(4-Chloro-phenyl)-5-trifluoromethyl-1H-imidazol-2-yl]-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyrimidine;4-(3-{4-[5-Cyclopropylmethyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-3-methyl-phenoxy)˜propyl)-1-methyl-piperidine;1-{4-[4-(4-Chtoro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-methyl-phenoxy}-3-(4-methyl-piperazin-1-yl)-propan-2-ol;4-(3-{3-Chloro-4-[4-(4-chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxyl}-propyl)-piperidine;4-(3-{3-Chloro-4-[4-(4-chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxyl}-propyl)-1-ethyl-piperidine;4-(3-{3-Chloro-4-[4-(4-chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-phenoxyl}-propyl)-1-isopropyl-piperidine;1-Methyl-4-{3-[4-4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-naphthalen-1-yloxy]-propyl}-piperidine;1-(4-Methyl-piperazin-1-yl)-3-{5-[5-methyl-4-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridin-2-yloxy}-propan-1-one;6-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-3-fluoro-2-[4-(1-methyl-piperidin-4-yl)-butoxy]-pyridine;1-Methyl-4-(4-{3-methyl-6-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridin-2-yloxyl}-butyl)-piperazine;1-Methyl-4-{3-[4-5-methyl-4-thiophen-2-yl-1H-imidazol-2-yl)-phenoxy]-propyl}-piperidine;2-{3-[4-1-Methyl-piperidin-4-yl)-butoxy]-phenyl}-3H-imidazo[4,5-b]pyridine;(5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5-Fluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5-Methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5,7-Difluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(7-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5,7-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(3,5-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(6-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(1H-Indol-2-yl)-(3-methyl-piperazin-1-yl)-methanone;(7-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5-Bromo-benzofuran-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(1H-Indol-2-yl)-(4-methyl-piperazin-1-yl)-methanethione;[5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;and[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amineand pharmaceutically acceptable salts thereof.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2009/079001:5-Fluoro-4-methyl-2-{4-methyl-1-[3-(1-methyl-piperidin-4-yl)-propyl]-2,3-dihydro-1H-indol-5-yl}-1H-benzoimidazole;4,5-Dimethyl-2-{4-methyl-1-[3-(1-methyl-piperidin-4-yl)-propyl]-2,3-dihydro-1H-indol-5-yl}-1H-benzoimidazole;2-{4-Chloro-1-[3-(1-methyl-piperidin-4-yl)-propyl]-2,3-dihydro-1H-indol-5-yl}-4,6-dimethyl-1H-benzoimidazole;2-{4-Chloro-1-[3-(1-methyl-piperidin-4-yl)-propyl]-2,3-dihydro-1H-indol-5-yl}-5-fluoro-4-methyl-1H-benzoimidazole;2-{4-Chloro-1-[3-(1-methyl-piperidin-4-yl)-propyl]-2,3-dihydro-1H-indol-5-yl}-1H-benzoimidazole-5-carboxylicacid methyl ester;5-Fluoro-2-{4-fluoro-1-[3-(1-methyl-piperidin-4-yl)-propyl]-2,3-dihydro-1H-indol-5-yl}-4-methyl-1H-benzoimidazole;5-Fluoro-4-methyl-2-{4-methyl-1-[3-(1-methyl-piperidin-4-yl)-propyl]-1H-indol-5-yl}-1H-benzoimidazole;2-{4-Chloro-1-[3-(1-methyl-piperidin-4-yl)-propyl]-1H-indol-5-yl}-5-fluoro-4-methyl-1H-benzoimidazole;2-{4-Chloro-1-[3-(1-methyl-pipehdin-4-yl)-propyl]-1H-indol-5-yl}-4,6-dimethyl-1H-benzoimidazole;5-Chloro-2-{4-methyl-1-[3-(1-methyl-piperidin-4-yl)-propyl]-1H-indol-5-yl}-1H-benzoimidazole;5-Fluoro-4-methyl-2-{1-[3-(1-methyl-piperidin-4-yl)-propyl]-1H-indol-5-yl}-1H-benzoimidazole;4-Methyl-2-{1-[3-(1-methyl-piperidin-4-yl)-propyl]-1H-indol-5-yl}-1H-benzoimidazole;5-Fluoro-4-methyl-2-{1-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-indol-5-yl}-1H-benzoimidazole;2-{2,3-Dimethyl-1-[3-(1-methyl-piperidin-4-yl)-propyl]-1H-indol-5-yl}-4,6-dimethyl-1H-benzoimidazole;2-{2,3-Dimethyl-1-[3-(1-methyl-piperidin-4-yl)-propyl]-1H-indol-5-yl}-5-fluoro-4-methyl-1H-benzoimidazole;5-Fluoro-4-methyl-2-{1-[4-(1-methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-1H-benzoimidazole;4-Chloro-2-{1-[4-(1-methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-1H-benzoimidazole;2-{1-[4-(1-Methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-5-trifluoromethyl-1H-benzoimidazole;6-{1-[4-(1-Methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-5H-[1,3]dioxolo[4′,5:4,5]benzo[1,2-d]-imidazole;(2-{1-[4-(1-Methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-1H-benzoimidazol-5-yl)-phenyl-methanone;2-{1-[4-(1-Methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-1H-naphtho[2,3-d]imidazole;6-Chloro-4-methyl-2-{1-[4-4-(1-methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-1H-benzoimidazole;4-Methyl-2-{1-[4-(1-methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-1H-benzoimidazole;5-tert-Butyl-2-{1-[4-(1-methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-1H-benzoimidazole;4,6-Dimethyl-2-{1-[4-(1-methyl-piperidin-4-yl)-butyl]-1H-indol-6-yl}-1H-benzoimidazole;5-Fluoro-4-methyl-2-{1-[4(1-methyl-piperidin-4-yl)-butyl]-1H-indol-6-yl}-1H-benzoimidazole;4-Methyl-2-{1-[4-(1-methyl-piperidin-4-yl)-butyl]-1H-indol-6-yl}-1H-benzoimidazole;5-tert-Butyl-2-{3-chloro-1-[3(1-methyl-piperidin-4-yl)-propyl]-1H-indol-5-yl}-1H-benzoimidazole;6-Chloro-2-{3-chloro-1-[3-(1-methyl-piperidin-4-yl)-propyl]-1H-indol-5-yl}-4-methyl-1H-benzoimidazole;2-{3-Chloro-1-[4-(1-methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-5-trifluoromethyl-1H-benzoimidazole;2-{3-Chloro-1-[4-(1-methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-5-fluoro-4-methyl-1H-benzoimidazole;2-{3-Chloro-1-[4-(1-methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-5,6-difluoro-1H-benzoimidazole;5-Fluoro-4-methyl-2-[1-(3-piperazin-1-yl-propyl)-1H-indol-5-yl]-1H-benzoimidazole;5-tert-Butyl-2-[3-chloro-1-(3-piperidin-4-yl-propyl)-1H-indol-5-yl]-1H-benzoimidazole;5-Fluoro-4-methyl-2-[1-(4-piperidin-4-yl-butyl)-1H-indol-4-yl]-1H-benzoimidazole;4-Chloro-2-[1-(4-piperidin-4-yl-butyl)-1H-indol-4-yl]-1H-benzoimidazole;4,6-Dimethyl-2-[1-(4-piperidin-4-yl-butyl)-1H-indol-6-yl]-1H-benzoimidazole;5-Fluoro-4-methyl-2-[1-(4-piperidin-4-yl-butyl)-1H-indol-6-yl]-1H-benzoimidazole;[5-(5-tert-Butyl-1H-benzoimidazol-2-yl)-1-(4-piperidin-4-yl-butyl)-1H-indol-3-ylmethyl]-dimethyl-amine;5-Fluoro-4-methyl-1′-[3-(1-methyl-piperidin-4-yl)-propyl]-1H,1′H-[2,5′]bibenzoimidazolyl;5-Fluoro-4-methyl-3′-[3-(1-methyl-piperidin-4-yl)-propyl]-1H,3H-[2,5′]bibenzoimidazolyl;4-Methyl-1′-[4-(1-methyl-piperidin-4-yl)-butyl]-1H,1′H-[2,5′]bibenzoimidazolyl;4-Methyl-3I-[4-(1-methyl-piperidin-4-yl)-butyl]-1H,3′H-[2,5′]bibenzoimidazolyl;5-Fluoro-4-methyl-1′-[4-(1-methyl-piperidin-4-yl)-butyl]-1H,1′H-[2,5′]bibenzoimidazolyl;5-Fluoro-4-methyl-3′-[4-(1-methyl-piperidin-4-yl)-butyl]-1H,3′H-[2,5′]bibenzoimidazolyl;5-Fluoro-4-methyl-2-{1-[3-(1-methyl-piperidin-4-yl)-propyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-1H-benzoimidazole;4,5-Dimethyl-2-{1-[3-(1-methyl-piperidin-4-yl)-propyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-1H-benzoimidazole;2-{6-Chloro-1-[3(1-methyl-piperidin-4-yl)-propyl]-1H-indol-5-yl}-4,6-difluoro-1H-benzoimidazole;2-[6-Chloro-1-(3-piperidin-4-yl-propyl)-1H-indol-5-yl]-5-fluoro-4-methyl-1H-benzoimidazole;2-{6-Chloro-1-[3-(1-methyl-piperidin-4-yl)-propyl]-1H-indol-5-yl}-5-fluoro-4-methyl-1H-benzoimidazole;5-Fluoro-4,4′-dimethyl-1′-[3-(1-methyl-piperidin-4-yl)-propyl]-1H,1′H-[2,5′]bibenzoimidazolyl;5,4′-Trimethyl-1′[3-(1-methyl-piperidin-4-yl)-propyl]-1H,1′H-[2,5′]bibenzoimidazolyl;4,4′-Dimethyl-1′-[3-(1-methyl-piperidin-4-yl)-propyl]-1H,1′H-[2,5]bibenzoimidazolyl;5-Chloro-4,4′-dimethyl-1′-[3-(1-methyl-piperidin-4-yl)-propyl]-1H,1′H-[2,5′]bibenzoimidazolyl;6-Fluoro-4,4′-dimethyl-1′-[3-(1-methyl-piperidin-4-yl)-propyl]-1H,1′H-[2,5]bibenzoimidazolyl;4,5-Dimethyl-2-[1-(3-piperidin-4-yl-propyl)-2,3-dihydro-1H-indol-5-yl]-1H-benzoimidazole;4,6-Dimethyl-2-{4-methyl-1-[3-(1-methyl-piperidin-4-yl)-propyl]-2,3-dihydro-1H-indol-5-yl}-1H-benzoimidazole;5-Chloro-2-{4-methyl-1-[3-(1-methyl-piperidin-4-yl)-propyl]-2,3-dihydro-1H-indol-5-yl}-1H-benzoimidazole;6-Fluoro-4-methyl-2-{4-methyl-1-[3-(1-methyl-piperidin-4-yl)-propyl]-2,3-dihydro-1H-indol-5-yl}-1H-benzoimidazole;2-Methyl-7-{4-methyl-1-[3(1-methyl-piperidin-4-yl)-propyl]-2,3-dihydro-1H-indol-5-yl}-6H-imidazo{4′,5′3,4]benzo[2,1-d]thiazole;4,6-Dimethyl-2-{4-methyl-1-[3-(1-methyl-piperidin-4-yl)-propyl]-1H-indol-5-yl}-1H-benzoimidazole;4,5-Dimethyl-2-[1-(3-piperazin-1-yl-propyl)-1H-indol-5-yl]-1H-benzoimidazole;5-tert-Butyl-2-[1-(3-piperazin-1-yl-propyl)-1H-indol-5-yl]-1H-benzoimidazole;5-Chloro-2-[1-(3-piperazin-1-yl-propyl)-1H-indol-5-yl]-1H-benzoimidazole;5-Chloro-2-{1-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-indol-5-yl}-1H-benzoimidazole;4-Methyl-2-[1-(4-piperidin-4-yl-butyl)-1H-indol-4-yl]-1H-benzoimidazole;5,6-Difluoro-2-{1-[4-(1-methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-1H-benzoimidazole;5-Chloro-2-{1-[4-(1-methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-1H-benzoimidazole;5-Fluoro-2-{1-[4-(1-methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-1H-benzoimidazole;4,6-Difluoro-2-{1-[4-(1-methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-1H-benzoimidazole;2-{1-[4-(1-Methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-1H-naphtho[1,2-d]imidazole;(2-{3-Chloro-1-[4-(1-methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-3H-benzoimidazol-4-yl)-phenyl-methanone;2-[3-Chloro-1-(4-piperidin-4-yl-butyl)-1H-indol-4-yl]-4,5-dimethyl-1H-benzoimidazole;2-{3-Chloro-1-[4-(1-methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-4,5-dimethyl-1H-benzoimidazole;2-{3-Chloro-1-[4-(1-methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-4,5-difluoro-1H-benzoimidazole;6-[1-(4-Piperidin-4-yl-butyl)-1H-indol-4-yl]-5H-[1.3dioxolo[4′,5′:4,5]-benzo[1,2-d]imidazole;Phenyl-{2-[1-(4-piperidin-4-yl-butyl)-1H-indol-4-yl]-1H-benzoimidazol-5-yl}-methanone;4,5-Dimethyl-2-{1-4-(1-methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-1H-benzoimidazole;1-[3-(4-Methyl-piperazin-1-yl)-propyl]-5-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-1H-indole;5-[4-(4-Chloro-phenyl)-5-methyl-1H-imidazol-2-yl]-1-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-indole;4-Methyl-1-[3-(1-methyl-piperidin-4-yl)-propyl]-5-(4-methyl-5-propyl-1H-imidazol-2-yl)-1H-benzoimidazole;4-Methyl-1-[3-(1-methyl-piperidin-4-yl)-propyl]-5-[4-methyl-5-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-1H-benzoimidazole;5-[5(3,5-Dichloro-phenyl)-4-methyl-1H-imidazol-2-yl]-4-methyl-1-[3-(1-methyl-piperidin-4-yl)-propyl]-1H-benzoimidazole;4-Methyl-1-[3-(1-methyl-piperidin-4-yl)-propyl]-5-(5-phenyl-4-trifluoromethyl-1H-imidazol-2-yl)-1H-benzoimidazole;5-[5-(4-Chloro-phenyl)-4-p-tolyl-1H-imidazol-2-yl]-4-methyl-1-[3-(1-methyl-piperidin-4-yl)-propyl]-1H-benzoimidazole;{5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-1-[3-(1-methyl-piperidin-4-yl)-propyl]-1H-indol-3-ylmethyl}-dimethyl-amine;2-[3-Chloro-1-(3-piperidin-4-yl-propyl)-1H-indol-5-yl]-5-fluoro-4-methyl-1H-benzoimidazole;2-{3-Chloro-1-[3-(1-methyl-piperidin-4-yl)-propyl]-1H-indol-5-y1}-5-fluoro-4-methyl-1H-benzoimidazole;2-[2,3-Dimethyl-1-(3-piperidin-4-yl-propyl)-1H-indol-5-yl]-4,6-dimethyl-1H-benzoimidazole;2-[2,3-Dimethyl-1-(3-piperidin-4-yl-propyl)-1H-indol-5-yl]-5-fluoro-4-methyl-1H-benzoimidazole;5-Fluoro-4-methyl-2-[1-(3-piperidin-4-yl-propyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-1H-benzoimidazole;5-tert-Butyl-2-{1-[3-(1-methyl-piperidin-4-yl)-propyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-1H-benzoimidazole;5-Fluoro-4-methyl-2-[1-(3-piperidin-4-yl-propyl)-2,3-dihydro-1H-indol-5-yl]-1H-benzoimidazole;5-Chloro-2-[1-(3-piperidin-4-yl-propyl)-2,3-dihydro-1H-indol-5-yl]-1H-benzoimidazole;4-Methyl-2-[1-(3-piperidin-4-yl-propyl)-2,3-dihydro-1H-indol-5-yl]-1H-benzoimidazole;5-Fluoro-4-methyl-2-{1-[3-(1-methyl-piperidin-4-yl)-propyl]-2,3-dihydro-1H-indol-5-yl}-1H-benzoimidazole;5-Chloro-2-{1-[3-(1-methyl-piperidin-4-yl)-propyl]-2,3-dihydro-1H-indol-5-yl}-1H-benzoimidazole;4-Methyl-2-{1-[3-(1-methyl-piperidin-4-yl)-propyl]-2,3-dihydro-1H-indol-5-yl}-1H-benzoimidazole;2-[6-Chloro-1-(3-piperidin-4-yl-propyl)-1H-indol-5-yl]-4,6-difluoro-1H-benzoimidazole;2-[6-Chloro-1-(3-piperidin-4-yl-propyl)-1H-indol-5-yl]-4,5-dimethyl-1H-benzoimidazole;5-Chloro-2-[6-chloro-1-(3-piperidin-4-yl-propyl)-1H-indol-5-yl]-1H-benzoimidazole;5-Chloro-2-{6-chloro-1-[3-(1-methyl-piperidin-4-yl)-propyl]-1H-indol-5-yl}-1H-benzoimidazole;2-{6-Chloro-1-[3-(1-methyl-piperidin-4-yl)-propyl]-1H-indol-5-yl}-4,5-dimethyl-1H-benzoimidazole;6-Chloro-4-methyl-2-[1-(4-piperidin-4-yl-butyl)-1H-indol-4-yl]-1H-benzoimidazole;5-tert-Butyl-2-[1-(4-piperidin-4-yl-butyl)-1H-indol-4-yl]-1H-benzoimidazole;6,7-Dimethyl-2-[1-(4-piperidin-4-yl-butyl)-1H-indol-4-yl]-1H-benzoimidazole;4-Methyl-2-[1-(4-pipehdin-4-yl-butyl)-1H-indol-6-yl]-1H-benzoimidazole;6-Chloro-4-methyl-2-[1-(4-piperidin-4-yl-butyl)-1H-indol-6-yl]-1H-benzoimidazole;5-tert-Butyl-2-[1-(4-piperidin-4-yl-butyl)-1H-indol-6-yl]-1H-benzoimidazole;4,5-Difluoro-2-[1-(4-piperidin-4-yl-butyl)-1H-indol-4-yl]-1H-benzoimidazole;4,4′-Dimethyl-1′-(3-piperidin-4-yl-propyl)-1H,1′H-[2,5I]bibenzoimidazolyl;6-Fluoro-4,4′-dimethyl-1′-(3-piperidin-4-yl-propyl)-1H,1′H-[2,5′]bibenzoimidazolyl;5-Chloro-4,4′-dimethyl-1′-(3-piperidin-4-yl-propyl)-1H,1′H-[2,5′]bibenzoimidazolyl;5-Fluoro-4,4′-dimethyl-1′-(3-piperidin-4-yl-propyl)-1H,1′H-[2,5′]bibenzoimidazolyl;5-Fluoro-2-[1-(4-piperidin-4-yl-butyl)-1H-indol-4-yl]-1H-benzoimidazole;4,6-Difluoro-2-[1-(4-piperidin-4-yl-butyl)-1H-indol-4-yl]-1H-benzoimidazole;4-Methyl-1′-(4-piperidin-4-yl-butyl)-1H,1′H-[2,5′]bibenzoimidazolyl;4,5-Dimethyl-1′-(4-piperidin-4-yl-butyl)-1H,1′H-[2,5′]bibenzoimidazolyl;5-Fluoro-1′-(4-piperidin-4-yl-butyl)-1H,1′H-[2,4′]bibenzoimidazolyl;5-Fluoro-1′-[4-(1-methyl-piperidin-4-yl)-butyl]-1H,1′H-[2,4′]bibenzoimidazolyl;4,5-Dimethyl-1′-[4-(1-methyl-piperidin-4-yl)-butyl]-1H,1′H-[2,5′]bibenzoimidazolyl;4-Methyl-3′-(4-piperidin-4-yl-butyl)-1H,3H-[2,5′]bibenzoimidazolyl;4,5-Dimethyl-3′-(4-piperidin-4-yl-butyl)-1H,3H-[2,5′]bibenzoimidazolyl;5-Fluoro-3′-(4-piperidin-4-yl-butyl)-1H,3H-[2,5]′bibenzoimidazolyl;4,5-Dimethyl-3′-[4-(1-methyl-piperidin-4-yl)-butyl]-1H,3H-[2,5′]bibenzoimidazolyl;5-Fluoro-3′-[4-(1-methyl-piperidin-4-yl)-butyl]-1H,3′H[2,5′]bibenzoimidazolyl;2-[1-(4-Piperidin-4-yl-butyl)-1H-indol-4-yl]-1H-naphtho[2,3-d]imidazole;2-[1-(4-Piperidin-4-yl-butyl)-1H-indol-4-yl]-1H-naphtho[1,2-d]imidazole;{2-[3-Chloro-1-(4-piperidin-4-yl-butyl)-1H-indol-4-yl]-1H-benzoimidazol-5-yl}-phenyl-methanone;2-[3-Chloro-1-(4-piperidin-4-yl-butyl)-1H-indol-4-yl]-5-trifluoromethyl-1H-benzoimidazole;2-[3-Chloro-1-(4-piperidin-4-yl-butyl)-1H-indol-4-yl]-5,6-difluoro-1H-benzoimidazole;2-[3-Chloro-1-(4-piperidin-4-yl-butyl)-1H-indol-4-yl]-4,5-difluoro-1H-benzoimidazole;2-[3-Chloro-1-(4-piperidin-4-yl-butyl)-1H-indol-4-yl]-5-fluoro-4-methyl-1H-benzoimidazole;7-[3-Chloro-1-(4-piperidin-4-yl-butyl)-1H-indol-4-yl]-2-methyl-8H-2-[3-Chloro-1-(4-piperidin-4-yl-butyl)-1H-indol-4-yl]-3H-benzoimidazole-5-carboxylicacid methyl ester;2-{3-Chloro-1-[4-(1-methyl-piperidin-4-yl)-butyl]-1H-indol-4-yl}-3H-benzoimidazole-5-carboxylicacid methyl ester;4,5,4′-Trimethyl-1′-(3-piperidin-4-yl-propyl)-1′H,1H-[2,5′]bibenzoimidazolyl;4,6-Dimethyl-2-[1-(4-piperidin-4-yl-butyl)-1H-indol-4-yl]-1H-benzoimidazole;6-Chloro-2-[1-(4-piperidin-4-yl-butyl)-1H-indol-4-yl]-1H-benzoimidazole;2-[1-(4-Piperidin-4-yl-butyl)-1H-indol-4-yl]-6-trifluoromethyl-1H-benzoimidazole;4-Methyl-1-[3-(1-methyl-piperidin-4-yl)-propyl]-5-[4-methyl-5-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-1H-benzoimidazole;5-[5-(4-Methoxy-phenyl)-4-methyl-1H-imidazol-2-yl]-4-methyl-1-[3-(1-methyl-piperidin-4-yl)-propyl]-1H-benzoimidazole;and pharmaceutically acceptable salts, prodrugs, and active metabolitesthereof.

In another particular embodiment, selective Histamine H4 antagonists areselected from those described in the international Patent ApplicationWO2009/038673:4-(4-Methyl-piperazin-1-yl)-thieno[3,2-d]pyrimidin-2-ylamine;4-(4-Methyl-piperazin-1-yl)-6,7,8,9-tetrahydro-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;4-Piperazin-1-yl-6,7,8,9-tetrahydro-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;4-[(3aR,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-(4-Methyl-piperazin-1-yl)-6,7,8,9-tetrahydro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-Piperazin-1-yl-6,7,8,9-tetrahydro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-[(3aR,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;4-(4-Methyl-piperazin-1-yl)-6,7,8,9-tetrahydro-benzo[4,5]furo[3,2-d]pyrimidine;4-Piperazin-1-yl-6,7,8,9-tetrahydro-benzo[4,5]furo[3,2-d]pyrimidine;4-(4-Methyl-piperazin-1-yl)-6,7,8,9-tetrahydro-benzo[4,5]thieno[3,2-d]pyrimidine;4-Piperazin-1-yl-6,7,8,9-tetrahydro-benzo[4,5]thieno[3,2-d]pyrimidine;7-Methyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]thieno[3,2-d]pyrimidin-2-amine;7-Methyl-4-(4-methylpiperazin-1-yl)thieno[3,2-d]pyrimidin-2-amine;7-Bromo-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]thieno[3,2-d]pyrimidin-2-amine;6-tert-Butyl-4-(4-methylpiperazin-1-yl)thieno[3,2-d]pyrimidin-2-amine;6-tert-Butyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]thieno[3,2-d]pyrimidin-2-amine;6-tert-Butyl-4-piperazin-1-ylthieno[3,2-d]pyrimidin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-6-tert-butylthieno[3,2-d]pyrimidin-2-amine;6-tert-Butyl-4-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)thieno[3,2-d]pyrimidin-2-amine;4-[(4aR,7aR)-Octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;4-(1,4-Diazepan-1-yl)-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;4-(3-Aminoazetidin-1-yl)-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;N4-(2-Aminoethyl)-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidine-2,4-diamine;4-(3,8-Diazabicyclo[3.2.1]oct-3-yl)6,7,8,9-tetrahydro[1]benzofuro[3,2d]pyrimidin-2-amine;N-(6,7,8,9-Tetrahydro[1]benzofuro[3,2d]pyrimidin-4-yl)ethane-1,2-diamine;(3R)—N-Methyl-1-(6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-4-yl)pyrrolidin-3-amine;N-(6,7,8,9-Tetrahydro[1]benzothieno[3,2-d]pyrimidin-4-yl)ethane-1,2-diamine;(3R)≥N-Methyl-1-(6,7,8,9-tetrahydrotilbenzothieno[3,2d]pyrimidin-4-yl)pyrrolidin-3-amine;4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[(4aR,7aR)-Octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[(3S)-3-Aminopiperidin-1-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[(1R,4R)-2,5-Diazabicyclo[2.2.1]hept-2-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-(1,4-Diazepan-1-yl)-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;(3S,4S)-1-(2-Amino-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-4-yl)-4-(methylamino)pyrrolidin-3-ol;4-[(3R)-3-(Dimethylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[(3R)-3-(Ethylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[(3R)-3-(Aminomethyl)pyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-(3-Aminoazetidin-1-yl)-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;8-Methyl-4-(4-methylpiperazin-1-yl)-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;8-Methyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;8-Methyl-4-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-(4-Methylpiperazin-1-yl)-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]thieno[3,2-d]pyrimidin-2-amine;4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]thieno[3,2-d]pyrimidin-2-amine;4-[(4aR,7aR)-Octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]thieno[3,2-d]pyrimidin-2-amine;4-[4-(2-Aminoethyl)piperazin-1-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[4-(1-Methylethyl)piperazin-1-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-(4-Ethylpiperazin-1-yl)-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-(Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-(Octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-(5,6-Dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[(3S)-3-(Methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;8,8-Difluoro-4-(4-methylpiperazin-1-yl)-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;8,8-Difluoro-4-piperazin-1-yl-6,7,8,9-tetrahydrotilbenzothieno[3,2d]pyrimidin-2-amine;8,8-Difluoro-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-(3,8-Diaza-bicyclo[3.2.1]oct-3-yl)-8-methoxy-6,7,8,9-tetrahydro-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;8-tert-Butyl-4-(4-methyl-piperazin-1-yl)-6,7,8,9-tetrahydro-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;4-[1,4]Diazepan-1-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;4-(3(S)-Amino-pyrrolidin-1-yl)-8-tert-butyl-6,7,8,9-tetrahydro-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;4-(3,8-Diazabicyclo[3.2.1]oct-3-yl)-8-methyl-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;8-tert-Butyl-4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;8-Methoxy-4-(4-methylpiperazin-1-yl)-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[3-(Aminomethyl)azetidin-1-yl]-8-tert-butyl-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-(3,4-Diazabicyclo[3.2.1]oct-3-yl)-8-methyl-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-8-methoxy-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-Piperazin-1-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;4-(4-Methylpiperazin-1-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;8-tert-Butyl-4-(4-methylpiperazin-1-yl)-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;8-Methyl-4-piperazin-1-yl-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;8-Methyl-4-(4-methylpiperazin-1-yl)-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;6,6-Dimethyl-4-(4-methylpiperazin-1-yl)-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-(1,4-Diazepan-1-yl)-8-methoxy-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;8-tert-Butyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-8-(trifluoromethyl)-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;4-[(3S)-3-Aminopyrrolidin-1-yl]-8-methoxy-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;8-Methoxy-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-8-(trifluoromethyl)-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-8-(trifluoromethyl)-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;4-[(3S)-3-Aminopyrrolidin-1-yl]-8-(trifluoromethyl)-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-8-methyl-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[(3S)-3-Aminopyrrolidin-1-yl]-8-methyl-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[3-(Aminomethyl)azetidin-1-yl]-8-methoxy-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[(3S)-3-Aminopyrrolidin-1-yl]-6,6-dimethyl-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-6,6-dimethyl-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;6,6-Dimethyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;4-[3-(Aminomethyl)azetidin-1-yl]-6,6-dimethyl-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;6,6-Dimethyl-4-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-6,7,8,9-tetrahydrorribenzothieno[3,2-d]pyrimidin-2-amine;8-tert-Butyl-4-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[(3aR,6aS)-5-Methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-8-(trifluoromethyl)-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;8-Methoxy-4-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[(3aR,6aS)-5-Methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-8-(trifluoromethyl)-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;8-Methyl-4-[(3ar,6aS)-5-methylhexahydropyrrol[3,4-c]pyrrol-2(1H)-yl]-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;4-(1,4-Diazepan-1-yl)-6,6-dimethyl-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;6,6-Dimethyl-4-piperazin-1-yl-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;6,6-Dimethyl-4-(4-methylpiperazin-1-yl)-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;N4-(2-Aminoethyl)-N4,6,6-trimethyl-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidine-2,4-diamine;N4-(2-Aminoethyl)-N4,6,6-trimethyl-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidine-2,4-diamine;N4-(2-Aminoethyl)-8-methoxy-N4-methyl-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidine-2,4-diamine;N4-(2-Aminoethyl)-8-methoxy-N4-methyl-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidine-2,4-diamine;N4-(2-Aminoethyl)-8-tert-butyl-N4-methyl-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidine-2,4-diamine;N4-(2-Aminoethyl)-8-tert-butyl-N4-methyl-6,7,8,9-tetrahydro[1]benzofuro[3,2-]pyrimidine-2,4-diamine;N4-(2-Aminoethyl)-N4-methyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidine-2,4-diamine;N4-(2-Aminoethyl)-N4-methyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidine-2,4-diamine;N4-(2-Aminoethyl)-N4,8-dimethyl-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidine-2,4-diamine;N4-(2-Aminoethyl)-N4,8-dimethyl-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidine-2,4-diamine;8,8-Difluoro-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-8,8-difluoro-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-(1,4-Diazepan-1-yl)-8,8-difluoro-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;N4-(2-Aminoethyl)-8,8-difluoro-N4-methyl-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidine-2,4-diamine;8,8-Difluoro-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-8,8-difluoro-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;8,8-Difluoro-4-piperazin-1-yl-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;4-[(3S)-3-Aminopyrrolidin-1-yl]-8,8-difluoro-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-(3-Aminoazetidin-1-yl)-8,8-difluoro-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;8,8-Difluoro-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;8,8-Difluoro-4-(4-methylpiperazin-1-yl)-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;4-((R,R)-octahydropyrrolo[3,4-b]pyridin-6-yl)-8,8-difluoro-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;N4-(2-Aminoethyl)-8,8-difluoro-N4-methyl-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidine-2,4-diamine;4-[(3S)-3-Aminopyrrolidin-1-yl]-8,8-difluoro-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;4-(3-Aminoazetidin-1-yl)-8,8-difluoro-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;N4-(2-Aminoethyl)-8,8-difluoro-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidine-2,4-diamine;8,8-Difluoro-4-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-(1,4-Diazepan-1-yl)-8,8-difluoro-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;8,8-Dimethyl-4-(4-methylpiperazin-1-yl)-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-(1,4-Diazepan-1-yl)-8,8-dimethyl-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;N4-(2-Aminoethyl)-N4,8,8-trimethyl-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidine-2,4-diamine;8,8-Dimethyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;8,8-Dimethyl-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-8,8-dimethyl-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;8,8-Dimethyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;4-(4-Methylpiperazin-1-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-8-tert-butyl-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;8-Methyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-8-(trifluoromethyl)-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;8-tert-Butyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[3-(Aminomethyl)azetidin-1-yl]-8-methyl-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-8-methyl-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;4-(1,4-Diazepan-1-yl)-8-methyl-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;8-Methyl-4-piperazin-1-yl-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-(3,8-Diazabicyclo[3.2.1]oct-3-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-Piperazin-1-yl-8-(trifluoromethyl)-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-(1,4-Diazepan-1-yl)-8-methyl-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;8-Methoxy-4-piperazin-1-yl-6,7,8,9-tetrahydro[1]benzothieno[3,2-d]pyrimidin-2-amine;4-(3,8-Diazabicyclo[3.2.1]oct-3-yl)-6,6-dimethyl-6,7,8,9-tetrahydro[1]benzofuro[3,2-d]pyrimidin-2-amine;and pharmaceutically acceptable salts, prodrugs, and active metabolitesthereof.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2008/100565:4-Cyclopentyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;4-Cyclopentyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;(R)-4-(3-Amino-piperidin-1-yl)-6-cyclopentyl-pyrimidin-2-ylamine;(R)-4-Cyclopentyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;trans-1-(2-Amino-6-cyclopentyl-pyrimidin-4-yl)-4-methylamino-pyrrolidin-3-ol;4-Cyclopentyl-6-(cis-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-pyrimidin-2-ylamine;4-Cyclopentyl-6-(cis-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine;4-Isopropyl-6-piperazin-1-yl-pyrimidin-2-ylamine;(R)-4-(3-Amino-piperidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine;(S)-4-(3-Amino-piperidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine;(R)-4-Isopropyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine;trans-1-(2-Amino-6-isopropyl-pyrimidin-4-yl)-4-methylamino-pyrrolidin-3-ol.;(S,S)-4-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-6-isopropyl-pyrimidin-2-ylamine;(R;R)-4-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-6-isopropyl-pyrimidin-2-ylamine;4-(cis-Hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-6-isopropyl-pyrimidin-2-ylamine;(R,R)-4-(Hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-6-isopropyl-pyrimidin-2-ylamine;4-Isopropyl-6-(cis-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine;4-Isopropyl-6-(cis-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine;(R,R)-4-Isopropyl-6-(cis-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine;(R)-4-Methyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;4-Methyl-6-(cis-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine;4,5-Dimethyl-6-piperazin-1-yl-pyrimidin-2-ylamine;4,5-Dimethyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-5,6-dimethyl-pyrimidin-2-ylamine;(R)-4,5-Dimethyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;4-(cis-Hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-5,6-dimethyl-pyrimidin-2-ylamine;4,5-Dimethyl-6-(cis-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine;4,5-Dimethyl-6-(cis-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine;(S,S)-4-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-5,6-dimethyl-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-ethyl-pyrimidin-2-ylamine;(R)-4-Ethyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;(R,R)-(4-Ethyl-6-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-pyrimidin-2-ylamine;4-Ethyl-6-(c/s-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine;(R,R)-(4-Ethyl-6-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine;4-Cyclopropyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;(R)-4-Cyclopropyl-6-3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;4-Cyclopropyl-6-(cis-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine;4-Cyclobutyl-6-piperazin-1-yl-pyrimidin-2-ylamine;4-Cyclobutyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;(R)-4-(3-Amino-piperidin-1-yl)-6-cyclobutyl-pyrimidin-2-ylamine;(R)-4-Cyclobutyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;4-Cyclobutyl-6-(cis-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-pyrimidin-2-ylamine;4-Cyclobutyl-6-(cis-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine;4-Cyclobutyl-6-(cis-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine;4-Cyclobutyl-6-(cis-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine;(R,R)-(4-Cyclobutyl-6-cis-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine;4-Cyclohexyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;(R)-(4-Cyclohexyl-6-3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;4-Cyclohexyl-6-(cis-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-pyrimidin-2-ylamine;(R,R)-4-Cyclohexyl-6-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine;4-Piperazin-1-yl-6-(tetrahydro-furan-3-yl)-pyrimidin-2-ylamine;4-(4-Methyl-piperazin-1-yl)-6-(tetrahydro-furan-3-yl)-pyrimidin-2-ylamine;4-Piperazin-1-yl-6-(tetrahydro-pyran-4-yl)-pyrimidin-2-ylamine;4-(4-Methyl-piperazin-1-yl)-6-(tetrahydro-pyran-4-yl)-pyrimidin-2-ylamine;(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-(tetrahydro-pyran-4-yl)-pyrimidin-2-ylamine;(R,R)-4-(Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6-(tetrahydro-pyran-4-yl)-pyrimidin-2-ylamine;4-Benzyl-6-piperazin-1-yl-pyrimidin-2-ylamine;4-Benzyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;(R)-Benzyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;(R,R)-4-Benzyl-6-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine;4-(4-Methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-quinazolin-2-ylamine;4-(4-Piperazin-1-yl)-5,6,7,8-tetrahydro-quinazolin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-5,6,7,8-tetrahydro-quinazolin-2-ylamine;(R)-4-(3-Methylamino-pyrrolidin-1-yl)-5,6,7,8-tetrahydro-quinazolin-2-ylamine;(R,R)-4-(Hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-5A7,8-tetrahydro-quinazolin-2-ylamine;4-(cis-Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-5,6,7,8-tetrahydro-quinazolin-2-ylamine;(R,R)-4-(Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-5,6,7,8-tetrahydro-quinazolin-2-ylamine;(S,S)-4-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-5,6,7,8-tetrahydro-quinazolin-2-ylamine;4-(4-Methyl-piperazin-1-yl)-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine;(R,R)-4-(4-Methylamino-pyrrolidin-1-yl-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine;4-tert-Butyl-6-piperazin-1-yl-pyrimidin-2-ylamine;4-tert-Butyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;(R)-4-tert-Butyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylannine;(R,R)-4-tert-Butyl-6-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-cyclopentyl-pyrimidin-2-ylamine;(R,R)-4-Cyclopentyl-6-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine;4-Cyclopentyl-6-(cis-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine;(R,R)-4-Cyclopentyl-6-(hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-pyrimidin-2-ylamine;4-Cyclopentyl-6-(cis-1,7-diaza-spiro[4.4]non-7-yl)-pyrimidin-2-ylamine;4-(3-Amino-azetidin-1-yl)-6-cyclopentyl-pyrimidin-2-ylamine;4-Cyclopentyl-6-(trans-hexahydro-pyrrolo[3,4-b][1,4]oxazin-6-yl)-pyrimidin-2-ylamine;4-Cyclopentyl-6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine;4-Cyclopentyl-6-(cis-hexahydro-pyrrolo[3,4-b][1,4]oxazin-6-yl)-pyrimidin-2-ylamine;(2-Amino-ethyl)-6-isopropyl-pyrimidine-2,4-diamine;4-(3-Amino-azetidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine;4-(1,7-Diaza-spiro[4.4]non-7-yl)-6-isopropyl-pyrimidin-2-ylamine;N4-(2-Amino-ethyl)-6-isopropyl-N4-methyl-pyrimidine-2,4-diamine;4-(cis-Hexahydro-pyrrolo[3,4-b][1,4]oxazin-6-yl)-6-isopropyl-pyrimidin-2-ylamine;4-(trans-Hexahydro-pyrrolo[3,4-b][1,4]oxazin-6-yl)-6-isopropyl-pyrimidin-2-ylamine;4-Isopropyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;4-(4-Methyl-piperazin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-ylamine;(R,R)-4-(Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-ylamine;(R)-4-(3-Methylamino-pyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-ylamine;4-Piperazin-1-yl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-ylamine;4-Butyl-5-methoxy-6-piperazin-1-yl-pyrimidin-2-ylamine;4-Butyl-6-[1,4]diazepan-1-yl-5-methoxy-pyrimidin-2-ylamine;4-(3-Amino-azetidin-1-yl)-6-butyl-5-methoxy-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-butyl-5-methoxy-pyrimidin-2-ylamine;(S)-4-(3-Amino-pyrrolidin-1-yl)-6-butyl-5-methoxy-pyrimidin-2-ylamine;(R)-4-Butyl-5-methoxy-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;(S)-4-Butyl-5-methoxy-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;4-Butyl-5-methoxy-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;N⁴-(2-Amino-ethyl)-6-butyl-5-methoxy-N4-methyl-pyrimidine-2,4-diamine;N⁴-(2-Amino-ethyl)-6-butyl-5-methoxy-pyrimidine-2,4-diamine;4-(3-Amino-azetidin-1-yl)-6-cyclopentyl-5-methoxy-pyrimidin-2-ylamine;4-Cyclopentyl-6-[1,4]diazepan-1-yl-5-methoxy-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-cyclopentyl-5-methoxy-pyrimidin-2-ylamine;(S)-4-Cyclopentyl-5-methoxy-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;N⁴-(2-Amino-ethyl)-6-cyclopentyl-5-methoxy-N⁴-methyl-pyrimidine-2,4-diamine;N⁴-(2-Amino-ethyl)-6-cyclopentyl-5-methoxy-pyrimidine-2I4-diamine;4-[1,4]Diazepan-1-yl)-6-methoxymethyl-pyrimidin-2-ylamine;(S)-4-(3-Amino-pyrrolidin-1-yl)-6-methoxymethyl-pyrimidin-2-ylamine;(S)-4-Methoxymethyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;4-Cyclopropyl-6-(cis-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine;4-Cyclopropyl-6-piperazin-1-yl-pyrimidin-2-ylamine;4-(3-Amino-azetidin-1-yl)-6-cyclopropyl-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-cyclopropyl-pyrimidin-2-ylamine;4-Cyclopropyl-6-(cis-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine;(S)-4-Isopropyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;(S)-4-(3-Amino-pyrrolidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-tert-butyl-pyrimidin-2-ylamine;4-tert-Butyl-6-(cis-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine;(S)-4-(3-Amino-pyrrolidin-1-yl)-6-tert-butyl-pyrimidin-2-ylamine;(S)-4-tert-Butyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;N4-(2-Amino-ethyl)-6-tert-butyl-N4-methyl-pyrimidine-2,4-diamine;4-tert-Butyl-6-(cis-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine;4-(3-Amino-azetidin-1-yl)-6-tert-butyl-pyrimidin-2-ylamine;4-tert-Butyl-6-(3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-butyl-pyrimidin-2-ylamine;4-Butyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;(R)-4-Butyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;N4-(2-Amino-ethyl)-6-butyl-N⁴-methyl-pyrimidine-2,4-diamine;4-Butyl-6-(cis-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine;Butyl-6-(cis-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine;4-Butyl-6-(cis-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine;4-Butyl-6-piperazin-1-yl-pyrimidin-2-ylamine;4-Butyl-6-(3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-ylamine;4-(4-Methyl-piperazin-1-yl)-6-propyl-pyrimidin-2-ylamine;4-(cis-5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-propyl-pyrimidin-2-ylamine;4-Isobutyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;4-Isobutyl-6-piperazin-1-yl-pyrimidin-2-ylamine;(R)-4-Isobutyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-isobutyl-pyrimidin-2-ylamine;(S)-4-Ethyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;(R)-4-Adamantan-1-yl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;4-Adamantan-1-yl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;4-(4-Methyl-tetrahydro-pyran-4-yl)-6-piperazin-1-yl-pyrimidin-2-ylamine;4-(4-Methyl-piperazin-1-yl)-6-(4-methyl-tetrahydro-pyran-4-yl)-pyrimidin-2-ylamine;(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-(4-methyl-tetrahydro-pyran-4-yl)-pyrimidin-2-ylamine;4-(trans-2-Phenyl-cyclopropyl)-6-piperazin-1-yl-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-(trans-2-phenyl-cyclopropyl)-pyrimidin-2-ylamine;4-(4-Methyl-piperazin-1-yl)-6-(trans-2-phenyl-cyclopropyl)-pyrimidin-2-ylamine;N4-(2-Amino-ethyl)-6-(trans-2-phenyl-cyclopropyl)-pyrimidine-2,4-diamine;(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-(trans-2-phenyl-cyclopropyl)-pyrimidin-2-ylamine;4-(3-Amino-azetidin-1-yl)-6-indan-2-yl-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-indan-2-yl-pyrimidin-2-ylamine;4-Indan-2-yl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;(R)-4-Indan-2-yl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;4-Indan-2-yl-6-piperazin-1-yl-pyrimidin-2-ylamine;4-(3-Amino-azetidin-1-yl)-6-benzyl-pyrimidin-2-ylannine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-benzyl-pyrimidin-2-ylamine;N4-(2-Amino-ethyl)-6-indan-2-yl-pyrimidine-2,4-diamine;(R)-4-(2,3-Dihydro-benzofuran-2-yl)-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;4-(cis-Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-(4-methyl-tetrahydro-pyran-4-yl)-pyrimidin-2-ylamine;4-(2,3-Dihydro-benzofuran-2-yl)-6-piperazin-1-yl-pyrimidin-2-ylamine;4-(3-Amino-azetidin-1-yl)-6-(2,3-dihydro-benzofuran-2-yl)-pyrimidin-2-ylamine;4-(cis-Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-indan-2-yl-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-(4-methyl-tetrahydro-pyran-4-yl)-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-(tetrahydro-pyran-4-yl)-pyrimidin-2-ylamine;N4-(2-Amino-ethyl)-6-(tetrahydro-pyran-4-yl)-pyrimidine-2, 4-diamine;N4-(2-Amino-ethyl)-N4-methyl-6-(tetrahydro-pyran-4-yl)-pyrimidine-2,4-diamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-phenethyl-pyrimidin-2-ylamine;4-(4-Methyl-piperazin-1-yl)-6-phenethyl-pyrimidin-2-ylamine;(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-phenethyl-pyrimidin-2-ylamine;4-(4-Methyl-piperazin-1-yl)-6-(3,3,3-trifluoro-propyl)-pyrimidin-2-ylamine;4-Piperazin-1-yl-6-(3,3,3-trifluoro-propyl)-pyrimidin-2-ylamine;(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-(3,3,3-trifluoro-propyl)-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-(3,3,3-trifluoro-propyl)-pyrimidin-2-ylamine;4-Cyclopentyl-5-methoxy-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;4-Cyclopentyl-5-methoxy-6-piperazin-1-yl-pyrimidin-2-ylamine;(R)-4-Cyclopentyl-5-methoxy-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;(R,R)-4-Cyclopentyl-5-methoxy-6-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine;N4-(2-Amino-ethyl)-N4-methyl-6-(tetrahydro-furan-3-yl)-pyrimidine-2,4-diamine;4-(cis-Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6-(tetrahydro-furan-3-yl)-pyrimidin-2-ylamine;(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-(tetrahydro-furan-3-yl)-pyrimidin-2-ylamine;4-[1,4]Diazepan-1-yl-6-(tetrahydro-furan-3-yl)-pyrimidin-2-ylamine;(−)-4-Piperazin-1-yl-6-(tetrahydro-furan-3-yl)-pyrimidin-2-ylamine;(+)-4-Piperazin-1-yl-6-(tetrahydro-furan-3-yl)-pyrimidin-2-ylamine;N4-(2-Amino-ethyl)-6-(tetrahydro-furan-3-yl)-pyrimidine-2,4-diamine;N4-(3-Amino-propyl)-6-(tetrahydro-furan-3-yl)-pyrimidine-2,4-diamine;N4-Methyl-N4-(2-methylamino-ethyl)-6-(tetrahydro-furan-3-yl)-pyrimidine-2,4-diamine;N4-(2-Methylamino-ethyl)-6-(tetrahydro-furan-3-yl)-pyrimidine-2,4-diamine;5-Fluoro-4-methyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;5-Fluoro-4-methyl-6-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine;5-Fluoro-4-methyl-6-piperazin-1-yl-pyrimidin-2-ylamine;(R)-5-Fluoro-4-methyl-6-(3-methylarnino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;N4-(2-Amino-ethyl)-5-fluoro-6,N4-dimethyl-pyrimidine-2,4-diamine;4-Piperazin-1-yl-6-pyridin-4-ylmethyl-pyrimidin-2-ylamine;(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-pyridin-4-ylmethyl-pyrimidin-2-ylamine;4-(4-Methyl-piperazin-1-yl)-6-pyridin-4-ylmethyl-pyrimidin-2-ylamine;4-(4-Methyl-piperazin-1-yl)-6-thiophen-3-ylmethyl-pyrimidin-2-ylamine;(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-thiophen-3-ylmethyl-pyrimidin-2-ylamine;4-Piperazin-1-yl-6-thiophen-3-ylmethyl-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-thiophen-3-ylmethyl-pyrimidin-2-ylamine;4-(cis-Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6-thiophen-3-ylmethyl-pyrimidin-2-ylamine;N⁴-(2-Amino-ethyl)-6-thiophen-3-ylmethyl-pyrimidine-2,4-diamine;4-(4-Methyl-piperazin-1-yl)-6-thiophen-2-ylmethyl-pyrimidin-2-ylamine;(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-thiophen-2-ylmethyl-pyrimidin-2-ylamine;4-Piperazin-1-yl-6-thiophen-2-ylmethyl-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-thiophen-2-ylmethyl-pyrimidin-2-ylamine;4-(cis-Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6-thiophen-2-ylmethyl-pyrimidin-2-ylamine;N⁴-(2-Amino-ethyl)-6-thiophen-2-ylmethyl-pyrimidine-2,4-diamine;N⁴-(2-Amino-ethyl)-6-methoxymethyl-pyrimidine-2,4-diamine;4-(3-Amino-azetidin-1-yl)-6-methoxymethyl-pyrimidin-2-ylamine;(R)-4-Methoxymethyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1yl)-6-methoxymethyl-pyrimidin-2-ylamine;4-Methoxymethyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;4-Methoxymethyl-6-piperazin-1-yl-pyrimidin-2-ylamine;(R)-4-(3-Amino-piperidin-1-yl)-6-methoxymethyl-pyrimidin-2-ylamine;(R,R)-4-Methoxymethyl-6-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine;4-(4-Methyl-piperazin-1-yl)-6-(tetrahydro-furan-2-ylmethyl)-pyrimidin-2-ylamine;(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-(tetrahydro-furan-2-ylmethyl)-pyrimidin-2-ylamine;4-(cis-5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-(tetrahydro-furan-2-ylmethyl)-pyrimidin-2-ylamine;4-Piperazin-1-yl-6-(tetrahydro-furan-2-ylmethyl)-pyrimidin-2-ylamine;4-(cis-Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6-(tetrahydro-furan-2-ylmethyl)-pyrimidin-2-ylamine;4-(4-Chloro-benzyl)-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;4-(4-Chloro-benzyl)-6-piperazin-1-yl-pyrimidin-2-ylamine;(R)-4-(4-Chloro-benzyl)-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-(4-chloro-benzyl)-pyrimidin-2-ylamine;4-(4-Chloro-benzyl)-6-(cis-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine;4-(4-Chloro-benzyl)-6-(cis-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine;N4-(2-Amino-ethyl)-6-(4-chloro-benzyl)-N4-methyl-pyrimidine-2,4-diamine;4-Ethyoxymethyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;4-Ethoxymethyl-6-piperazin-1-yl-pyrimidin-2-ylamine;(R)-Ethoxymethyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;(R)-Ethoxymethyl-6-(3-amino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;Isopropoxymethyl-6-((R)-3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylarnine;4-Isopropoxymethyl-6-piperazin-1-yl-pyrimidin-2-ylamine;(R)-Isopropoxymethyl-6-(3-amino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;4-Isopropoxymethyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;4-Phenethyl-6-piperazin-1-yl-pyrimidin-2-ylamine;4-(3-Amino-azetidin-1-yl)-6-phenethyl-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-(tetrahydro-pyran-4-yl)-pyrimidin-2-ylamine;N⁴-(2-Amino-ethyl)-6-benzyl-N4-methyl-pyrimidine-2,4-diamine;4-Indan-2-yl-6-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine;4-(3-Amino-azetidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-ylamine;4-(3-Amino-azetidin-1-yl)-5,6,7,8-tetrahydro-quinazolin-2-ylamine;4-(cis-5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-ylamine;(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-phenyl-cyclopropyl)-pyrimidin-2-ylamine(diastereomer 1);(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-(2-phenyl-cyclopropyl)-pyrimidin-2-ylamine(diastereomer 2);4-Cyclopentyl-6-(cis-1,7-diaza-spiro[4.4]non-7-yl)-pyrimidin-2-ylamine(enantiomer 1);4-Cyclopentyl-6-(cis-1,7-diaza-spiro[4.4]non-7-yl)-pyrimidin-2-ylamine(enantiomer 2);(R)-4-Isopropoxymethyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-isopropoxymethyl-pyrimidin-2-ylamine;4-Isopropoxymethyl-6-piperazin-1-yl-pyrimidin-2-ylamine;4-Isopropoxymethyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;4-(3-Amino-azetidin-1-yl)-6-isopropoxymethyl-pyrimidin-2-ylamine;4-Isopropoxymethyl-6-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-ylamine;(R)-4-Cyclopropoxymethyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;(R)-(4-Amino-pyrrolidin-1-yl)-6-cyclopropoxymethyl-pyrimidin-2-ylamine;4-Cyclopropoxymethyl-6-piperazin-1-yl-pyrimidin-2-ylamine;4-Cyclopropoxymethyl-6-(4-methyl-piperazin-1-yl)-pyhmidin-2-ylamine;4-(3-Amino-azetidin-1-yl)-6-cyclopropoxymethyl-pyrimidin-2-ylamine;4-Cyclopropoxymethyl-6-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-ylamine;(R)-4-tert-Butoxymethyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-6-tert-butoxymethyl-pyhmidin-2-ylamine;4-tert-Butoxymethyl-6-piperazin-1-yl-pyrimidin-2-ylamine;4-tert-Butoxymethyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine;4-(3-Amino-azetidin-1-yl)-6-tert-butoxymethyl-pyrimidin-2-ylamine;4-tert-Butoxymethyl-6-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-ylamine;4-Ethyl-6-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-ylamine;4-(8-Methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-6-propyl-pyrimidin-2-ylamine;4-Isopropyl-6-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-ylamine;4-Cyclopentyl-6-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-ylamine;and pharmaceutically acceptable salts thereof.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2008/008359:8-Chloro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;6,8-Dichloro-4-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Chloro-4-(4-isopropyl-[1,4]diazepan-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(3-Amino-pyrrolidin-1-yl)-6,8-dichloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-6,8-Dichloro-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-4-(3-Methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Chloro-4-[1,4]diazepan-1-yl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Chloro-4-(octahydro-pyrido[1,2-a]pyrazin-2-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Chloro-8-(otahydro-pyrrolo[3,4-b]pyridin-6-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Chloro-4-(4-methyl-[1,4]diazepan-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S,S)-8-Chloro-4-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Chloro-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S)-4-(3-Amino-piperidin-1-yl)-8-chloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Chloro-4-piperazin-1-yl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Chloro-4-(3-dimethylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(3-Amino-pyrrolidin-1-yl)-8-chloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S)-8-Chloro-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-8-Chloro-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-8-Bromo-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Bromo-4-(hexahydro-pyrrolo[1,2-a]jpyrazin-2-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(3-Amino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-4-(3-Dimethylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-Piperazin-1-yl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-8-Chloro-4-(3-dimethylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-8-chloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S)-4-(3-Aminomethyl-pyrrolidin-1-yl)-8-chloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Chloro-4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-4-(3-Amino-piperidin-1-yl)-8-chloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(3-Aminomethyl-pyrrolidin-1-yl)-8-chloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-4-(3-Aminomethyl-pyrrolidin-1-yl)-8-chloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;6,8-Dichloro-4-piperazin-1-yl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;6,8-Dichloro-4-[1,4]diazepan-1-yl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S,S)-4-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-benzo[415]furo[3,2-d]pyrimidin-2-ylamine;8-Chloro-4-(4-isopropyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;6,8-Dichloro-4-(3-dimethylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(Octahydro-pyrido[1,2-a]pyrazin-2-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;6,8-Dichloro-4-(octahydro-pyrido[1,2-a]pyrazin-2-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S,S)-6,8-Dichloro-4-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-8-Fluoro-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Fluoro-4-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Fluoro-N⁴-methyl-N⁴-(1-methyl-pyrrolidin-3-yl)-benzo[4,5]furo[3,2-d]pyrimidine-2,4-diamine;(R)-8-(3-Methylamino-pyrrolidin-1-yl)-9-oxa-1,5,7-triaza-fluoren-6-ylamine;8-(Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-9-oxa-1,5,7-triaza-fluoren-6-ylamine;4-(4-Methyl-piperazin-1-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;8-Bromo-4-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;7-Bromo-4-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;(S)-8-Bromo-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;(R)-8-Bromo-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;(S,S)-8-Bromo-4-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;8-Bromo-4-(4-methyl-piperazin-1-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;(S)-4-(3-Methylamino-pyrrolidin-1-yl)-7-trifluoromethyl-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;(R)-4-(3-Methylamino-pyrrolidin-1-yl)-7-trifluoromethyl-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;(S,S)-4-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-7-trifluoromethyl-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;4-(4-Methyl-piperazin-1-yl)-7-trifluoromethyl-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;7-Bromo-4-(4-methyl-piperazin-1-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;(R)-7-Bromo4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;(S)-7-Bromo-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;4-(Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-7-trifluoromethyl-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;7-Chloro-4-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;(R)-7-Chloro-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;(S)-7-Chloro-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;(S,S)-7-Chloro-4-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-benzo[415]thieno[3,2-d]pyrimidin-2-ylamine;7-Chloro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;8-Chloro-4-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;(S)-8-Chloro-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;(R)-8-Chloro-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;8-Chloro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;(S,S)-8-Chloro-4-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;8-Chloro-4-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Fluoro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;8-Fluoro-4-(hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S)-8-Chloro-4-(3-ethylamino-piperidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-8-Chloro-4-(3-ethylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S)-8-Chloro-4-(3-methylamino-piperidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S)-8-Chloro-4-(3-dimethylamino-piperidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-8-Fluoro-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;(S,S)-7-Bromo-4-(2,5-diaza-bicyclop[2.2.1]hept-2-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;4-(6-Amino-3-aza-bicyclo[3.1.0]hex-3-yl)-8-chloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-4-(2-Aminomethyl-pyrrolidin-1-yl)-8-chloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Chloro-4-(hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R,R)-8-Chloro-4-(2,6-diaza-bicyclo[2.2.1]hept-2-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R,R)-8-Chloro-4-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Chloro-4-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-4-(3-Methylamino-pyrrolidin-1-yl)-9-trifluoromethyl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S,S)-4-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-9-methoxy-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;9-Methoxy-4-piperazin-1-yl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S)-4-(3-Amino-piperidin-1-yl)-9-methoxy-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;9-Methoxy-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Methoxy-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-Piperazin-1-yl-9-trifluoromethyl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(4-Methyl-piperazin-1-yl)-9-trifluoromethyl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S)-4-(3-Amino-piperidin-1-yl)-9-trifluoromethyl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S)-4-(3-Amino-piperidin-1-yl)-8,9-dichloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S,S)-4-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-9-trifluoromethyl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(cis)-8-Chloro-4-(hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;N4-(2-Amino-ethyl)-8-chloro-N4-methyl-benzo[4,5]furo[3,2-d]pyrimidine-2,4-diamine;8-Chloro-4-(3,8-diaza-bicyclo[3.2.1]oct-3-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S,S)-8,9-Dichloro-4-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-8,9-Dichloro-4(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-9-Methoxy-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8,9-Dichloro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-8-Methoxy-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(3-Aminomethyl-azetidin-1-yl)-8-chloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8,9-Dichloro-4-piperazin-1-yl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(cis)-8-Methoxy-4-(octahydro-pyrrolo[3,4-b]pyridin-6-yl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S,S)-8-Chloro-4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S)-4-(3-Amino-piperidin-1-yl)-8-methoxy-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-4-(3-Amino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-3-Chloro-8-(3-methylamino-pyrrolidin-1-yl)-9-oxa-1,5,7-triaza-fluoren-6-ylamine;N⁴-Azetidin-3-ylmethyl-8-chloro-benzo[4,5]furo[3,2-d]pyrimidine-2,4-diamine;N⁴-Azetidin-3-yl-8-chloro-benzo[4,5]furo[3,2-d]pyrimidine-2,4-diamine;N⁴-(2-Amino-ethyl)-8-chloro-benzo[4,5]furo[3,2-d]pyrimidine-2,4-diamine;(S,S)-4-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-8-methoxy-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(cis)-4-(Hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-8-methoxy-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;2-[8-Chloro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamino]-ethanol;2-[4-(4-Methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamino]-ethanol;(cis)-2-[8-Chloro-4-octahydro-pyrrol[3,4-b]pyridin-6-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamino]-ethanol;2-[8-Methoxy-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamino]-ethanol;[8-Chloro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-cyclopropyl-amine;[8-Chloro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-isobutyl-amine;Allyl-[8-chloro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-amine;N¹-[8-Chloro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-propane-1,3-diamine;[8-Chloro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-(2-methylsulfanyl-ethyl)-amine;[8-Chloro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-methyl-amine;(S,S)-2-[8-Chloro-4-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamino]-ethanol;2-[8-Chloro-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamino]-ethanol;2-[8-Chloro-4-(4-methyl-[1,4]diazepan-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamino]-ethanol;8-Chloro-4-(3,5-dimethyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(3-Amino-azetidin-1-yl)-8-chloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(2S,5R)-8-Chloro-4-(2,5-dimethyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S)-8-Chloro-4-(2-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d3pyrimidin-2-ylamine;(R)-8-Chloro-4-(2-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S)-8-Chloro-4-(5-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-8-Chloro-4-(5-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;9-Fluoro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-9-Fluoro-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;9-Fluoro-4-piperazin-1-yl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(3-Amino-azetidin-1-yl)-9-fluoro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(4-Methyl-piperazin-1-yl)-8-trifluoromethyl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-4-(3-Methylamino-pyrrolidin-1-yl)-8-trifluoromethyl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S)-4-(3-Amino-piperidin-1-yl)-8-trifluoromethyl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-Piperazin-1-yl-8-trifluoromethyl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S,S)-4,2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-8-trifluoromethyl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(3-Amino-azetidin-1-yl)-8-trifluoromethyl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8,9-Difluoro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8,9-Difluoro-4-piperazin-1-yl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S)-4-(3-Amino-piperidin-1-yl)-8,9-difluoro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-8,9-Difluoro-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S,S)-4-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-8,9-difluoro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(3-Amino-azetidin-1-yl)-8,9-difluoro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;9-Chloro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-9-Chloro-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;9-Chloro-4-piperazin-1-yl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S)-4-(3-Amino-piperidin-1-yl)-9-chloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S,S)-9-Chloro-4-(2I5-diaza-bicyclo[2.2.1]hept-2-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(3-Amino-azetidin-1-yl)-9-chloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(R)-7-Methoxy-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;(S)-7-Methoxy-4-(3-methylamino-pyrrolidin-1-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;7-Methoxy--(4-methyl-piperazin-1-yl)-benzo[4,5]thieno[3,2-d]pyrimidin-2-ylamine;(S)-2-[4-(3-Amino-piperidin-1-yl)-8-chloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamino]-ethanol;2-(8-Chloro-4-piperazin-1-yl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamino)-ethanol;2-[4-(3-Amino-azetidin-1-yl)-8-chloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamino]-ethanol;[8-Chloro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-dimethyl-amine;and pharmaceutically acceptable salts thereof.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2009077608:4-Cyclohexyloxymethyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-Cyclohexyloxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-(Cyclopropylmethoxymethyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-(Cyclopropylmethoxymethyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-Cyclobutoxymethyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-Cyclobutoxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-Cyclopentoxymethyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-annine;4-Cyclopentoxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-Isopropoxymethyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-Isopropoxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-Isobutoxymethyl-6-(3-(methylannino)azetidin-1-yl)pyrimidin-2-amine;4-Isobutoxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-(2,2-Dimethylpropoxymethyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-(2,2-Dimethylpropoxynnethyl)-6-((3R)-3-(methylannino)pyrrolidin-1-yl)pyrimidin-2-amine;4-tert-Butoxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-(Cyclopentylmethoxymethyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-(Cyclopentylmethoxymethyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-(((1S,2R,4R)-Bicyclo[2.2.1]heptan-2-yloxy)methyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-(((1S,2R,4R)-Bicyclo[2.2.1]heptan-2-yloxy)methyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidine-2-amine;4-Benzyloxymethyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-Benzyloxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;6-Methoxymethyl-4-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;6-Methoxymethyl-4-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-(3-(Methylamino)azetidin-1-yl)-6-phenoxymethylpyrimidin-2-amine;6-(2-Methoxyethyl)4-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-(4-Fluorophenoxymethyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-(2,4-Difluorophenoxymethyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-(3,4-Difluorophenoxymethyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-(2,4-Difluorophenoxymethyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-(3,4-Difluorophenoxymethyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-(3-Aminoazetidin-1-yl)-6-isopropoxymethylpyrimidin-2-amine;4-((3R)-3-Aminopyrrolidin-1-yl)-6-isopropoxynnethylpyrimidin-2-amine;4-(3-(Methylamino)azetidin-1-yl)-6-(tetrahydropyran-4-yl)pyrimidin-2-amine;4-(3-(Methylamino)azetidin-1-yl)-6-((S)-tetrahydrofuran-2-yl)pyrimidin-2-amine;4-((3R)-3-(Methylamino)pyrrolidin-1-yl)-6-((S)-tetrahydrofuran-2-yl)pyrimidin-2-amine;4-(3-(Methylamino)azetidin-1-yl)-6-((R)-tetrahydrofuran-2-yl)pyrimidin-2-amine;4-((3R)-3-(Methylamino)pyrrolidin-1-yl)-6-((R)-tetrahydrofuran-2-yl)pyrimidin-2-amine;4-(2-(4-Chlorophenoxy)propan-2-yl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-(2-(4-Chlorophenoxy)propan-2-yl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;6-((R)-1-Methoxyethyl)-4-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-(3-(Methylamino)azetidin-1-yl)-6-((R)-phenyl(methoxy)methyl)pyrimidin-2-amine;4-((3R)-3-(Methylamino)pyrrolidin-1-yl)-6-((R)-phenyl(methoxy)methyl)pyrimidin-2-amine;4-(3-(Methylamino)azetidin-1-yl)-6-((S)-phenyl(methoxy)methyl)pyrimidin-2-amine;4-Cyclohexyloxymethyl-6-[3-methyl-3-(methylamino)azetidin-1-yl]pyrimidin-2-amine;4-Isobutoxymethyl-6-[3-methyl-3-(methylamino)azetidin-1-yl]pyrimidin-2-amine;4-Isopropoxymethyl-6-[3-methyl-3-(methylamino)azetidin-1-yl]pyrimidin-2-amine;4-(1,1-Dimethyl-2-methoxyethyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-(2-Isopropoxyethyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-(1-(Methoxymethyl)cyclopentyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-[3-Methyl-3-(methylamino)azetidin-1-yl]-6-[(2S)-tetrahydrofuran-2-yl]pyrimidin-2-amine;4-[(Dicyclopropylmethoxy)methyl]-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-(1-(Methoxymethyl)cyclopentyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;Methyl3-(((2-amino-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-yl)methoxy)nnethyl)benzoate;Methyl-4-(((2-amino-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-yl)methoxy)methyl)benzoate;Methyl-2-(((2-amino-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-yl)methoxy)nnethyl)benzoate;4-(3-(Methylamino)azetidin-1-yl)-6-((4-(methylsulfonyl)benzyloxy)methyl)pyrimidin-2-amine;4-(3-(Methylamino)azetidin-1-yl)-6-((3-(methylsulfonyl)benzyloxy)methyl)pyrimidin-2-amine;2-[3-(((2-Amino-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-yl)methoxy)methyl)phenyl]propan-2-ol;[3-(((2-Amino-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-yl)methoxy)methyl)phenyl]methanol;[4-(((2-Amino-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-yl)methoxy)methyl)phenyl]methanol;[2-(((2-Amino-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-yl)methoxy)methyl)phenyl]methanol;3-[((2-Amino-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-yl)methoxy)methyl]benzoicacid;3-[((2-Amino-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-yl)methoxy)methyl]benzamide;and3-R(2-Amino-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-yl)methoxy)methyl]-N-butylbenzamide,or a salt thereof.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2009/056551:4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2-d]pyrimidin-2-amine;4-[3-(Methylamino)azetidin-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2-d]pyrimidin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2-d]pyrimidin-2-amine;4-(3-Aminoazetidin-1-yl)-6,7,8,9-tetrahydrobenzofuro[3,2-d]pyrimidin-2-amine;4-[(4aR,7aR)-Octahydro-6H-pyrrolo[3,4-b]pyrimidin-6-yl]-6,7,8,9-tetrahydrobenzofuro[3,2-d]pyrimidin-2-amine;4-[3-Methyl-3-(Methylamino)azetidin-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2-d]pyrimidin-2-amine;4-Piperazin-1-yl-6,7,8,9-tetrahydrobenzofuro[3,2-d]pyrimidin-2-amine;4-(1,4-Diazepan-1-yl)-6,7,8,9-tetrahydrobenzofuro[3,2-d]pyrimidin-2-amine;4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2-d]pyrimidine;4-[3-(Methylamino)azetidin-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2-d]pyrimidine;4-(1,4-Diazepan-1-yl)-6,7,8,9-tetrahydrobenzofuro[3,2-d]pyrinnidine;4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]furo[3,2-d]pyrimidin-2-amine;4-[3-(Methylamino)azetidin-1-yl]-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]furo[3,2-d]pyrimidin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]furo[3,2-d]pyrimidin-2-amine;4-[3-Methyl-3-(methylamino)azetidin-1-yl]-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]furo[3,2-d]pyrimidin-2-amine;4-[3-(Methylamino)azetidin-1-yl]-7,8-dihydro-6H-cyclopenta[4,5]furo[3,2-d]pyrimidin-2-amine;4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-7,8-dihydro-6H-cyclopenta[4,5]furo[3,2-d]pyrimidin-2-amine;N⁴-[(3R)-1-(Methylpyrrolidin-3-yl]amino-6,7,8,9-tetrahydrobenzofuro[3,2-d]pyrimidine-2,4-diamine;4-(4-Methylpiperazin-1-yl)-6,7,8,9-tetrahydrobenzofuro[3,2-d]pyrimidin-2-amine;(S)-4-(3-Methylpiperazin-1-yl)-6,7,8,9-tetrahydrobenzofuro[3,2-d]pyrimidin-2-amine;and4-(4-Methylpiperazin-1-yl)-6,7,8,9-tetrahydrobenzofuro[3,2-d]pyrimidinand salts thereof.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2009/068512:4-(Cyclopropylmethyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-Cyclopropylmethyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-Cyclopropylmethyl-6-((3R)-3-aminopyrrolidin-1-yl)pyrimidin-2-amine;4-Cyclopropylmethyl-6-(piperazin-1-yl)pyrimidin-2-amine;4-Cyclopropylmethyl-6-(3-methyl-3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-(3-Aminoazetidin-1-yl)-6-cyclopropylmethyl-pyrimidin-2-amine;4-Cyclopropylmethyl-6-(1,4-diazepan-1-yl) pyrimidin-2-amine;4-(4-Aminopiperidin-1-yl)-6-cyclopropylmethyl-pyrimidin-2-amine;4-Cyclopropylmethyl-6-((4aR,7aR)-octahydropyrrolo[3,4-b]pyridine-6-yl)pyrimidin-2-amine;4-Cyclopropylmethyl-6-((3S)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;(R)-4-Cyclopropylmethyl-6-[(N-methylpyrrolidin-3-yl)amine]pyrimidin-2-amine;(S)-4-Cyclopropylmethyl-6-(3-methylpiperazin-1-yl)pyrimidin-2-amine;(R)-4-Cyclopropylmethyl-6-(3-methylpiperazin-1-yl)pyrimidin -2-amine;4-Cyclopropylmethyl-6-[3-(pyrrolidin-1-yl)azetidin-1-yl]pyrimidin-2-amine;4-(Cyclopropylmethyl)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-2-amine;(S)-4-(Cyclopropylmethyl)-6-(hexahydropyrrolo[1,2-a)]-2(1H)-yl)pyrimidin-2-amine;4-Isopropyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-Isopropyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-tert-Butyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-tert-Butyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-(3-(Methylamino)azetidin-1-yl)-6-propylpyrimidin-2-amine;4-((3R)-3-(Methylamino)pyrrolidin-1-yl)-6-propylpyrimidin-2-amine;4-Cyclopropyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-Cyclopropyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-Ethyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-Ethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-Butyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-Butyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-Cyclopentylmethyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-Cyclopentylmethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-Isobutyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-Isobutyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-(2,2-Dimethylpropyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-(2,2-Dimethylpropyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;trans-4-(2-Phenylcyclopropyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;(R)-4-tert-Butyl-6-[(N-methylpyrrolidin-3-yl)amine]pyrimidin-2-amine;4-(2-Cyclopentylethyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-(2-Cyclopentylethyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-annine;4-(2-Cyclopropylethyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-((3R)-3-(Methylamino)pyrrolidin-1-yl)-6-(4-methylpentyl)pyrimidin-2-amine;4-(3-(Methylamino)azetidin-1-yl)-6-(4-methylpentyl)pyrimidin-2-amine;4-(3-Cyclopentylpropyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-(4-Cyclohexylbutyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine;4-(4-Cyclohexylbutyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;(S)-4-(2-Cyclopropylethyl)-6-(3-methylpiperazin-1-yl)pyrimidin-2-amine;4-(3-Aminoazetidin-1-yl)-6-(cyclopentylmethyl)pyrimidin-2-amine;4-(3-(Methylamino)azetidin-1-yl)-6-(2,2,3,3-tetramethylcyclopropyl)pyrimidin-2-amine;4-Cyclobutyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-Cyclopentyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-((3R)-3-(Methylamino)pyrrolidin-1-yl)-6-(2,2,3,3-tetramethylcyclopropyl)pyrimidin-2-amine;4-Isobutyl-6-(3-methyl-3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-(3-Methyl-3-(methylamino)azetidin-1-yl)-6-neopentylpyrimidin-2-amine;(S)-4-(3-Methylpiperazin-1-yl)-6-neopentylpyrimidin-2-amine;4-(3-(Methylamino)azetidin-1-yl)-6-(1-methylcyclopropyl)pyrimidin-2-amine;(R)-4-(Cyclopropylmethyl)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-2-amine;4-Cyclopentyl-6-(3-methyl-3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-Cyclobutyl-6-(3-methyl-3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;4-(3-Methyl-3-(methylamino)azetidin-1-yl)-6-(2,2,3,3-tetramethylcyclopropyl)pyrimidin-2-amine;(S)-4-(3-Methylpiperazin-1-yl)-6-(2,2,3,3-tetramethylcyclopropyl)pyrimidin-2-amine;4-(3-(Methylamino)azetidin-1-yl)-6-(pentan-3-yl)pyrimidin-2-amine;4-((3R)-3-(Methylamino)pyrrolidin-1-yl)-6-(pentan-3-yl)pyrimidin-2-amine;4-((1S,2S,4S)-Bicyclo[2.2.1]heptan-2-yl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;and4-((1S,2R,4S)-Bicyclo[2.2.1]heptan-2-yl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amineand salts thereof.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2009/080721:2-Isobutyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-amine;2-Cyclohexylmethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-amine;2-(4-Fluorobenzyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine;2-Isobutyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine;2-Cyclopropyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine;2-tert-Butyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine;2-Isopropyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine;2-(Cyclopropylmethyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine;6-(3-(Methylamino)azetidin-1-yl)-2-(phenoxymethyl)pyrimidin-4-amine;2-Cyclopropyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-amine;2-tert-Butyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-amine;2-Isopropyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-amine;6-((3R)-3-(Methylamino)pyrrolidin-1-yl)-2-(phenoxymethyl)pyrimidin-4-amine;6-(3-Aminoazetidin-1-yl)-2-isobutylpyrimidin-4-amine;2-Isobutyl-6-(3-methyl-3-(methylamino)azetidin-1-yl) pyrimidin-4-amine;6-((3R)-3-aminopyrrolidin-1-yl)-2-isobutylpyrimidin-4-amine;2-Cyclobutyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine;2-Cyclobutyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-amine;2-Cyclopentyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine;2-Cyclopentyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-amine;2-(2,2-Dimethylpropyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine;2-(2,2-Dimethylpropyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-amine;2-(2-Cyclopentylethyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-amine;2-Cyclohexylmethyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine;2-Cyclopropylmethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-amine;2-Cyclohexyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine;2-Cyclohexyl-6-((3R)-3-(methylannino)pyrrolidin-1-yl)pyrimidin-4-amine;and2-(4-Fluorobenzyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-amine,or a salt thereof.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2009/115496:7-Cyclopropyl-4-(4-methylpiperazin-1-yl)furo[3,2-d]pyrimidin-2-amine;7-Cyclopropyl-4-[(3S)-(3-methylpiperazin-1-yl)furo[3,2-d]pyrimidin-2-amine;7-Ethyl-4-[4-methylpiperazin-1-yl)furo[3,2-d]pyrimidin-2-amine;4-[4-methylpiperazin-1-yl)-7-propylfuro[3,2-d]pyrimidin-2-amine;7-Cyclopropyl-4-(3-(methylamino)azetidin-1-yl)furo[3,2-d]pyrimidin-2-amine;7-Cyclopropyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl)furo[3,2-d]pyrimidin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl)-7-cyclopropylfuro[3,2-d]pyrimidin-2-amine;4-(3-Aminoazetidin-1-yl)-7-cyclopropylfuro[3,2-d]pyrimidin-2-amine;7-Cyclopropyl-4-(3-methyl-3-(methylamino)azetidin-1-yl)furo[3,2-d]pyrimidin-2-amine;7-Cyclopropyl-4-(piperazin-1-yl)furo[3,2-d]pyrimidin-2-amine;7-Cyclopropyl-4-(1,4-diazepan-1-yl)furo[3,2-d]pyrimidin-2-amine;7-Ethyl-4-(3-(methylamino)azetidin-1-yl)furo[3,2-d]pyrimidin-2-amine;7-Ethyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl)furo[3,2-d]pyrimidin-2-amine;4-[(3R)-3-Aminopyrrolidin-1-yl]-7-ethylfuro[3,2-d]pyrimidin-2-amine;7-Ethyl-4-(3-methyl-3-(methylamino)azetidin-1-yl)furo[3,2-d]pyrimidin-2-amine;7-Ethyl-4-(piperazin-1-yl)furo[3,2-d]pyrimidin-2-amine;4-(3-(Methylamino)azetidin-1-yl)-7-propylfuro[3,2-d]pyrimidin-2-amine;4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-7-propylfuro[3,2-d]pyrimidin-2-amine;4-[(3R)-3-(Aminopyrrolidin-1-yl)-7-propylfuro[3,2-d]pyrimidin-2-amine;4-(3-Methyl-3-(methylamino)azetidin-1-yl]-7-propylfuro[3,2-d]pyrimidin-2-amine;4-(Piperazin-1-yl]-7-propylfuro[3,2-d]pyrimidin-2-amine;7-Isopropyl-4-(3-(methylamino)azetidin-1-yl]furo[3,2-d]pyrimidin-2-amine;7-Isopropyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]furo[3,2-d]pyrimidin-2-amine;7-Benzyl-4-(3-(methylamino)azetidin-1-yl]furo[3,2-d]pyrimidin-2-amine;7-Benzyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]furo[3,2-d]pyrimidin-2-amine;7-Cyclobutyl-4-(3-(methylamino)azetidin-1-yl)furo[3,2d]pyrimidin-2-amine;7-Cyclobutyl-4-[(3R)-3-methylamino)pyrrolidin-1-yl)furo[3,2d]pyrimidin-2-amine;7-Cyclopentyl-4-(3-(methylamino)azetidin-1-yl)furo[3,2d]pyrimidin-2-amine;7-Cyclopentyl-4-[(3R)-3-methylamino)pyrrolidin-1-yl)furo[3,2d]pyrimidin-2-amine;7-Isobutyl -4-(3-(methylamino)azetidin-1-yl)furo[3,2d]pyrimidin-2-amine;7-Isobutyl-4-[(3R)-3-methylamino)pyrrolidin-1-yl)furo[3,2d]pyrimidin-2-amine;4-(3-(Methylamino)azetidin-1-yl)-7-phenylfuro[3,2d]pyrimidin-2-amine;4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-7-phenylfuro[3,2d]pyrimidin-2-amine;7-tert-butyl-4-(3-(methylamino)azetidin-1-yl)furo[3,2d]pyrimidin-2-amine;7-tert-butyl-4-[(3R)-3-methylamino)pyrrolidin-1-yl)furo[3,2d]pyrimidin-2-amine;7-Cyclopropyl-4-(3-(methylamino)azetidin-1-yl)furo[3,2d]pyrimidin-2-amine;6-Chloro-7-cyclobutyl-4-(3-(methylamino)azetidin-1-yl)furo[3,2-d]pyrimidin-2-amine;6-Chloro-7-cyclopropyl-4-(3-(methylamino)azetidin-1-yl)furo[3,2-d]pyrimidin-2-amine;6-Chloro-7-cyclopropyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]furo[3,2-d]pyrimidin-2-amine;6-Chloro-7-isopropyl-4-(3-(methylamino)azetidin-1-yl)furo[3,2-d]pyrimidin-2-amine;6-Chloro-7-isopropyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]furo[3,2-d]pyrimidin-2-amine;6-Chloro-7-cyclopentyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]furo[3,2-d]pyrimidin-2-amine;4-(3-(Methylamino)azetidin-1-yl)-7-(tetrahydro-2H-pyran-4-yl)furo[3,2-d]pyrimidin-2-amine;2-Amino-7-isopropyl-4-((3R)-3-(methylamino)pyrrolidin-1-yl)furo[3,2-d]pyrimidine-6-carbonitrile;2-Amino-7-cyclopropyl-4-(3-(methylamino)azetidin-1-yl)furo[3,2-d]pyrimidine-6-carbonitrile;7-(1-(Methoxymethyl)cyclopropyl)-4-(3-(methylamino)azetidin-1-yl)furo[3,2-d]pyrimidin-2-amineand salts thereof.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2007/090852:[(R)-1-(2-Amino-8-chlorobenzo[4,5]furo[3,2-d]-pyrimidin-4-yl)pyrrolidin-3-yl]N-methylamine;[(S)-1-(2-Amino-8-chlorobenzo[4,5]furo[3,2-d]-pyrimidin-4-yl)pyrrolidin-3-yl]N-methylamine;[1-(2-Ethylamino-8-chlorobenzo[4,5]furo[3,2-d]-pyrimidin-4-yl)azetidin-3-yl]N-ethylamine;4-((R)-3-Methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Methyl-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Fluoro-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Bromo-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;7-Chloro-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;N-[1-(2-Amino-8-chlorobenzo[4,5]furo[3,2-d]pyrimidin-4-yl)azetidin-3-yl]N-methylamine;4-(3-Methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Bromo-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Methyl-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Fluoro-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Methoxy-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-((R)-3-Methylamino-pyrrolidin-1-yl)-8-trifluoromethoxy-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;9-Fluoro-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;9-Methyl-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;9-Methoxy-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;7-Methyl-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;7-Methoxy-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-((R)-3-Methylamino-pyrrolidin-1-yl)-7-trifluoromethyl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;6-Chloro-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;6-Methyl-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;6-Methoxy-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Methoxy-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(3-Methylamino-azetidin-1-yl)-8-trifluoromethoxy-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;9-Fluoro-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;9-Methyl-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;9-Methoxy-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;7-Methyl-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;7-Methoxy-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(3-Methylamino-azetidin-1-yl)-7-trifluoromethyl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;6-Chloro-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;6-Methyl-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;6-Methoxy-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Chloro-4-[3-(cyclopropylmethyl-amino)-pyrrolidin-1-yl]-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Chloro-4-((R)-3-dimethylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-((R)-3-Amino-pyrrolidin-1-yl)-8-chloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Chloro-4-(4-methylamino-piperidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(4-Amino-piperidin-1-yl)-8-chloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(3-Amino-azetidin-1-yl)-8-chloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;[8-Chloro-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-methyl-amine;[8-Chloro-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-dimethyl-amine;N-[8-Chloro-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-acetamide;N-[8-Chloro-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-methanesulfonamide;[8-Chloro-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-cyclopropyl-amine;[8-Chloro-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-methyl-amine;[8-Chloro-4-(3-methylamino-azetidin-1-yl)benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-dimethyl-amine;N-[8-Chloro-4-(3-methylamino-azetidin-1-yl)benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-acetamide;

N-[8-Chloro-4-(3-methylamino-azetidin-1-yl)benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-methanesulfonamide;[8-Chloro-4-(3-methylamino-azetidin-1-yl)benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-cyclopropyl-amineand salts thereof.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2007/090853:[(R)-1-(2-Amino-8-chlorobenzo[4,5]furo[3,2-d]-pyrimidin-4-yl)pyrrolidin-3-yl]N-methylamine;4-((R)-3-Methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Methyl-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Fluoro-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Bromo-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;7-Chloro-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Methoxy-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-((R)-3-Methylamino-pyrrolidin-1-yl)-8-trifluoromethoxy-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;9-Fluoro-4-((R)-3-methylamino-pyrrolidin-1I-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;9-Methyl-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;9-Methoxy-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;7-Methyl-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;7-Methoxy-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-((R)-3-Methylamino-pyrrolidin-1-yl)-7-trifluoromethyl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;6-Chloro-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;6-Methyl-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;6-Methoxy-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Chloro-4-[3-(cyclopropylmethyl-amino)-pyrrolidin-1-yl]-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Chloro-4-((R)-3-dimethylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-((R)-3-Amino-pyrrolidin-1-yl)-8-chloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;[8-Chloro-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-methyl-amine;[8-Chloro-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-dimethyl-amine;N-[8-Chloro-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-acetamide;N-[8-Chloro-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-methanesulfonamide;[8-Chloro-4-((R)-3-methylamino-pyrrolidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-cyclopropyl-amine.Some of said compounds and/or salts or esters thereof, will exist indifferent stereoisomeric forms. All of these forms are subjects of theinvention, provided that the amino group attached to the pyrrolidinering in 4-position of the pyrimidine ring shows R-configuration.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2007/090854:[1-(2-Ethylamino-8-chlorobenzo[4,5]furo[3,2-d]-pyrimidin-4-yl)azetidin-3-yl]N-ethylamine;N-[1-(2-Amino-8-chlorobenzo[4,5]furo[3,2-d]pyrimidin-4-yl)azetidin-3-yl]N-methylamine;4-(3-Methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Bromo-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Methyl-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Fluoro-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Methoxy-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(3-Methylamino-azetidin-1-yl)-8-trifluoromethoxy-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;9-Fluoro-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;9-Methyl-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;9-Methoxy-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;7-Methyl-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;7-Methoxy-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(3-Methylamino-azetidin-1-yl)-7-trifluoromethyl-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;6-Chloro-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;6-Methyl-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;6-Methoxy-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(3-Amino-azetidin-1-yl)-8-chloro-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;[8-Chloro-4-(3-methylamino-azetidin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-methyl-amine;[8-Chloro-4-(3-methylamino-azetidin-1-yl)benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-dimethyl-amine;N-[8-Chloro-4-(3-methylamino-azetidin-1-yl)benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-acetamide;N-[8-Chloro-4-(3-methylamino-azetidin-1-yl)benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-methanesulfonamide;[8-Chloro-4-(3-methylamino-azetidin-1-yl)benzo[4,5]furo[3,2-d]pyrimidin-2-yl]-cyclopropyl-amine.Some of said compounds and/or salts or esters thereof, will exist indifferent stereoisomeric forms

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2007/039467:N-[(R,S)-1-(8-Chloro-2-methylbenzo[4,5]furo[3,2-d]-pyrimidin-4-yl)-pyrrolidin-3-yl]-N-methylamine;N-[(R,S)-1-(8-Chlorobenzo[4,5]furo[3,2-d]-pyrimidin-4-yl)-pyrrolidin-3-yl]-N-methylamine;[(R,S)-1-(8-Chloro-2-methylbenzo[4,5]furo[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl]dimethyl amine;N—[(R)-1-(8-chlorobenzo[4,5]furo[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl]N-methyl amine;N—[(S)-1-(8-chlorobenzo[4,5]furo[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl]N-methyl amine;N-[1-(8-chlorobenzo[4,5]furo[3,2-d]pyrimidin-4-yl)azetidin-3-yl] amine;N-[1-(8-chlorobenzo[4,5]furo[3,2-d]pyrimidin-4-yl)azetidin-3-ylN-methylamine;N-1-(8-Chlorobenzo[4,5]furo[3,2-d]pyrimidin-4-yl)azetidin-3-yl]N,N-dimethylamine;N-[1-(8-Chlorobenzo[4,5]furo[3,2-d]pyrimidin-4-yl)azetidin-3-yl]N,N-dimethylamine;[(R,S)-1-(8-chlorobenzo[4,5]furo[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl]amine;[(R,S)-1-(8-chlorobenzo[4,5]furo[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl]dimethylamine;[(R,S)-1-(8-methylbenzo[4,5]furo[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl]-N-methylamine;[(R)-1-(8-chlorobenzo[4,5]furo[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl]amine;[(S)-1-(8-chlorobenzo[4,5]furo[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl];N-[(R)-1-(8-trifluoromethylbenzo[4,5]furo[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl]N-methylamine;N—[(S)-1-(8-trifluoromethylbenzo[4,5]furo[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl]N-methylamine;N—[(R)-1-(8-methylbenzo[4,5]furo[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl]N-methylamine;N—[(S)-1-(8-methylbenzo[4,5]furo[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl]N-methylamine;N-[(R)-1-(8-chloro-2-trifluoromethylbenzo[4,5]furo[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl]N-methylamine;N—[(S)-1-(8-chloro-2-trifluoromethylbenzo[4,5]furo[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl]N-methylamine;N-[1-(8-chlorobenzo[4,5]furo[3,2-d]pyrimidin-4-yl)azetidin-3-yl]N-ethylamine;[(R,S)-1-(8-chlorobenzo[4,5]furo[3,2-d]pyrimidin-4-yl)-3-methylpyrrolidin-3-yl]-N-methylamine;N-[1-(8-chlorobenzo[4,5]furo[3,2-d]pyrimidin-4-yl)azetidin-3-yl]N-cyclopropylamine; and[(3RS,4RS)-1-(8-chlorobenzo[4,5]furo[3,2-d]pyrimidin-4-yl)-4-fluoropyrrolidin-3-yl]N-methylamine. Some of said compounds and/or salts or esters thereof, will existin different stereoisomeric forms.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2009/071625:10-[(3R)-1-azabicyclo[2.2.2]oct-3-ylmethyl]-10H-phenothiazine(dextrorotatory enantiomer);10-[(3S)-1-azabicyclo[2.2.2]oct-3-ylmethyl]-10H-phenothiazine(levorotatory enantiomer); the racemic mixture of the two enantiomers10-[(3R,3S)-1-azabicyclo[2.2.2]oct-3-ylmethyl]-10H-phenothiazine.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2009/134726:4-piperazin-1-yl-5,6,7a,8,9,10,11,11a-octahydro[1]benzofuro[2,3-h]quinazolin-2-amine;4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-5,6,7a,8,9,10,11,11a-octahydro[1]benzofuro[2,3-h]quinazolin-2-amine;(7aS,11aS)-4-piperazin-1-yl-5,6,7a,8,9,10,11,11a-octahydro[1]benzofuro[2,3-h]quinazolin-2-amine;(7aR,11aR)-4-piperazin-1-yl-5,6,7a,8,9,10,11,11a-octahydro[1]benzofuro[2,3-h]quinazolin-2-amine;4-(4-methyl-1,4-diazepan-1-yl)-5,6,7a,8,9,10,11,11a-octahydro[1]benzofuro[2,3-h]quinazolin-2-amine;4-(4-methylpiperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydro[1]benzofuro[2,3-h]quinazolin-2-amine;4-[(3R)-3-aminopyrrolidin-1-yl]-7a,8,9,10,11,11a-hexahydro[1]benzofuro[2,3-h]quinazolin-2-amine;4-[(1R,5S)-3,6-diazabicyclo[3.2.0]hept-6-yl]-7a,8,9,10,11,11a-hexahydro[1]benzofuro[2,3-h]quinazolin-2-amine;4-(1,4-diazepan-1-yl)-5,6,7a,8,9,10,11,11a-octahydro[1]benzofuro[2,3-h]quinazolin-2-amine;4-(4-isopropyl-1,4-diazepan-1-yl)-5,6,7a,8,9,10,11,11a-octahydro[1]benzofuro[2,3-h]quinazolin-2-amine;4-(4-cyclobutyl-1,4-diazepan-1-yl)-5,6,7a,8,9,10,11,11a-octahydro[1]benzofuro[2,3-h]quinazolin-2-amine;trans-4-piperazin-1-yl-5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolin-2-amine;cis-4-piperazin-1-yl-5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolin-2-amine;trans-4-[3-(methylamino)azetidin-1-yl]-5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolin-2-amine;trans-4-[3-(ethylamino)azetidin-1-yl]-5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolin-2-amine;trans-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolin-2-amine;trans-4-[(3R)-3-aminopyrrolidin-1-yl]-5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolin-2-amine;trans-4-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl-5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolin-2-amine;cis-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolin-2-amine;cis-4-[(3R)-3-aminopyrrolidin-1-yl]-5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolin-2-amine;cis-4-[cis-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolin-2-amine;cis-4-[3-(methylamino)azetidin-1-yl]-5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolin-2-amine;cis-4-[3-(ethylamino)azetidin-1-yl]-5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolin-2-amine;4-cis-octahydro-6H-pyrrolo[3,4-6]pyridin-6-yl-6,7,7a,8,11,11a-hexahydro-5H-8,11-ethanobenzo[6,7]cyclohepta[1,2-d]pyrimidin-2-amine;4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-6,7,7a,8,11,11a-hexahydro-5H-8,11-ethanobenzo[6,7]cyclohepta[1,2-d]pyrimidin-2-amine;4-piperazin-1-yl-6,7,7a,8,11,11a-hexahydro-5H-8,11-ethanobenzo[6,7]cyclohepta[1,2-d]pyrimidin-2-amine;4-cis-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl-6,7,7a,8,9,10,11,11a-octahydro-5H-8,11-ethanobenzo[6,7]cyclohepta[1,2-d]pyrimidin-2-amine;or4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-6,7,7a,8,9,10,11,11a-octahydro-5H-8,11-ethanobenzo[6,7]cyclohepta[1,2-d]pyrimidin-2-amine.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2009/114575:(R)-4′-(3-(methylamino)pyrrolidin-1-yl)-6′,7′-dihydro-5H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;4′-(piperazin-1-yl)-6′,7′-dihydro-5H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;4′-(3-(methylamino)azetidin-1-yl)-6′,7′-dihydro-5H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;(R)-4′-(3-aminopyrrolidin-1-yl)-6′7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;(S)-4′-(3-aminopyrrolidin-1-yl)-6′7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;4′-((3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-6I,7I-dihydro-5H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;4′-((3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-6′7′-dihydro-5H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;4′-(1,4-diazepan-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;4′-((4aR,7aR)-tetrahydro-1H-pyrrolo[3,4-b]pyridin-6(2H,7H,7aH)-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;N4′-(1-methylpiperidin-4-yl)-6′,7′-dihydro-5H-spiro[cyclopentane-1,8′-quinazoline]-2′,4′-diamine;methyl4-amino-1-(2′-amino-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazoline]-4′-yl)piperidine-4-carboxylate;4-amino-1-(2′-amino-6′,7′-dihydro-5H-spiro[cyclopentane-1,8′-quinazoline]-4′-yl)piperidine-4-carboxylicacid;4′-(3-aminoazetidin-1-yl)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;4′-(2-(dimethylamino)ethoxy)-6′,7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;(R)-4′-(1-methylpyrrolidin-3-yloxy)-6′7′-dihydro-5′H-spiro[cyclopentane-1,8′-quinazolin]-2′-amine;4-(piperazin-1-yl)-5,6,7,8-tetrahydrospiro[cyclohepta[d]pyrimidine-9,1′-cyclohexan]-2-amine;(R)-4-(3-aminopyrrolidin-1-yl-5,6,7,8-tetrahydrospiro[cyclohepta[d]pyrimidine-9,1′-cyclohexan]-2-amine;4-((4aR,7aR)-tetrahydro-1H-pyrrolo[3,4-b]pyridin-6(2H,7H,7aH)-yl)-5,6,7,8-tetrahydrospiro[cyclohepta[d]pyrimidine-9,1′-cyclohexan]-2-amine;4-(piperazin-1-yl)-1′,3′,5,6,7,8-hexahydrospiro[cyclohepta[d]pyrimidine-9,2′-inden]-2-amine;and(R)-4-(3-aminopyrrolidin-1-yl)-1′,3′,5,6,7,8-hexahydrospiro[cyclohepta[d]pyrimidine-9,2′-inden]-2-amine.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2008/060767:6-Methyl-4-[(3R)-3-methylamino-pyrrolidin-1-yl]-5,6-dihydro-benzo[h]quinazolin-2-ylamine;6-Methyl-4-(3-methylamino-azetidin-1-yl)-5,6-dihydro-benzo[h]quinazolin-2-ylamine;4-(3-Methylamino-azetidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;6-Methyl-4-piperazin-1-yl-5,6-dihydro-benzo[h]quinazolin-2-ylamine;4-(3-(R)-Methylamino-pyrrolidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cydohepta[1,2-d]pyrimidin-2-ylamine;4-Piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;1-(3-Methylamino-azetidin-1-yl)-10H-9-oxa-2,4-diaza-phenanthren-3-ylamine;1-{3-(R)-Methylamino-pyrrolidin-1-yl)-10H-9-oxa-2,4-diaza-phenanthren-3-ylamine;1-Piperazin-1-yl-10H-9-oxa-2,4-diaza-phenanthren-3-ylamine;10-Fluoro-4-(3-(R)-methylamino-pyrrolidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;10-Fluoro-4-(3-methylamino-azetidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;10-Fluoro-4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;4-[(3S)-3-Methylamino-pyrrolidin-1-yl]-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;4-((3aR,6aR)-1-Methyl-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;4-((3R)-3-Amino-pyrrolidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;4-((1S,4S)-2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-6,7-dihydro-5H-benzo[6,7]cyciohepta[1,2-d]pyrimidin-2-ylamine;4-(3-Piperidin-1-yl-pyrrolidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;4-{(3aR,6aR)-Hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;4-Piperazin-1-yl-5,6,7,8-tetrahydro-1,3-diaza-dibenzo[a,c]cycloocten-2-ylamine;4-Piperazin-1-yl-6,7,8,9-tetrahydro-5H-1,3-diaza-dibenzo[a,c]cyclononen-2-ylamine;4-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;4-{3-(R)-Methylamino-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-1,3-diaza-dibenzo[a,c]cyclononen-2-ylamine;4-({R)-3-Amino-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-1,3-diaza-dibenzo[a,c]cyclononen-2-ylamine;4-{(S)-3′Amino-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-1,3-diaza-dibenzo[a,c]cyclononen-2-ylamine;4-(3-Methylamino-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-1,3-diaza-dibenzo[a,c]cyclononen-2-ylamine;4-{(3aS,6aS)-Hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-6,7,8,9-tetrahydro-5H-1,3-diaza-dibenzo[a,c]cyc1ononen-2-ylamine;4-((1S,4S)-2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-6,7,8,9-tetrahydro-5H-1,3-diaza-dibenzo[a,c]cyclononen-2-ylamine;4-{4-Methyl-piperazin-1-yl)-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;4-Piperazin-1-yl-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;4-((R)-3-Methylamino-pyrrolidin-1-yl)-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine,4-(3-Methylamino-azetidin-1-yl)-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;4-(3-Methylamino-azetidin-1-yl)-5,6-dihydro-7-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;4-(3-(R)-Methylamino-pyrrolidin-1-yl)-5,6-dihydro-7-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;4-{3-(R)-Amino-pyrrolidin-1-yl)-5,6-dihydro-7-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;4-Piperazin-1-yl-5,6-dihydro-7-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;4-(3-Methylamino-azetidin-1-yl)-7-oxo-6,7-dihydro-5H-7λ4-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;4-(3-Methylamino-azetidin-1-yl)-7,7-dioxo-6,7-dihydro-5H-7λ6-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;4-(3-(R)-Methylamino-pyrrolidin-1-yl)-5,6-dihydro-benzo[h]quinazolin-2-ylamine;4-(3-Methylamino-azetidin-1-yl)-5t6-dihydro-benzo[h]quinazolin-2-ylamine;4-Piperazin-1-yl-5,6-dihydro-benzo[h]quinazolin-2-ylamine;10-chloro-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-5,6-dihydro[1]benzoxepino[5,4-d]pyrimidin-2-amine;10-methyl-4-[(3R)-3-{methylamino)pyrrolidin-1-yl]-5,6-dihydro[1]benzoxepino[5,4-of]pyrimidin-2-amine;10-methoxy-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-5,6-dihydro[1]benzoxepino[5,4-d]pyrimidin-2-amine;9-chloro-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-5,6-dihydro[1]benzoxepino[5,4-d]pyrimidin-2-amine;9-nrrethyl-4-[{3R)-3-(methylamino)pyrrolidin-1-yl]-5,6′-dihydro[1]benzoxepino[5,4-d]pyrimidin-2-amine;9-methoxy-4-[(3R)-3-{methylamino)pyrrolidin-1-yl]-5,6-dihydro[1]benzoxepino[5,4-d]pyrimidin-2-amine;8-chloro-4-[(3R)-3-(methylamino)pyrrolidin-1yl]-5,6-dihydro[1]benzoxepino[5,4-d]pyrimidin-2-amine;8-Methyl-4-((R)-3-methylamino-pyrrolidin-1-yl)-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;8-methoxy-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-5,6-dihydro[1]benzoxepino[5,4-d]pyrimidin-2-amine;4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydrobenzo[7,8]cycloocta[1,2-d]pyrimidin-2-amine;4-[(3R)-3-aminopyrrolidin-1-yl]-5,6,7,8-tetrahydrobenzo[7,8]cycloocta[1,2-d]pyrimidin-2-amine;4-[(3S)-3-aminopyrroiidin-1-yl]-5,6,7,8-tetrahydrobenzo[7,8]cycloocta[1,2-d]pyrimidin-2-amine;4-(3-aminoazetidin-1-yl)-5,6,7,8-tetrahydrobenzo[7,8]cycloocta[1,2-d]pyrimidin-2-amine;4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]-5,6,7,8-tetrahydrobenzo[7,8]cycloocta[1,2-d]pyrimidin-2-amine;4-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-amine;4-(2,8-diazaspiro[4.5]dec-8-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-amine;4-(1,5-diazocan-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-amine;4-{4-aminopiperidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-amine;N4-(2-azetidin-2-ylethyl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,4-diamine;N4-[(2R)-azetidin-2-ylmethyl]-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,4-diamine;N4-(1-methylpiperidin-4-yl)-6,7-dihydro-5H-benzo[6,7]cycloheptat[1,2-d]pyrimidine-2,4-diamine;N4-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,4-diamine;4-(5-methyl-1,4-diazepan-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-amine;4-(1-Methyl-piperidin-4-yloxy)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;4-(1-methyl-piperidin-3-yloxy)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;4-((R)-1-Methyl-pyrrolidin-3-yloxy)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;4-((S)-1-Methyl-pyrrolidin-3-yloxy)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine,4-(Piperidin-4-yloxy)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;4-((S)-Pyrrolidin-3-yloxy)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine,4-(2-Dimethylamino-ethoxy)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;4-(1,9-Diaza-spiro[5.5]undec-9-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;4-((R)-3-Dimethylamino-pyrrolidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;4-(2,6-Diaza-spiro[3.5]non-2-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;4-(2,5-Diaza-spiro[3.5]non-2-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;4-(Octahydro-pyrrolo[3,4-c]pyridin-2-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;4-(Octahydro-pyrrolo[1,2-a]pyrazin-2-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;4-(3,6-Diaza-bicyclo[3.2.1]oct-6-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;4-(2,6-Diaza-bicyclo[3.2.1]oct-2-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;N-(4-Piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-acetamide,N-(4-Piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-benzamide,4-(5-Methyl-octahydro-pyrrolo[3,4-c]pyridin-2-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine,4-(3-Methyl-3,6-diaza-bicyclo[3.2.1]oct-6-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine,2-Dimethylamino-N-(4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-acetamide;2-Methylamino-N-(4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-acetamide;2-Amino-N-(4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-acetamide;1-Methyl-3-(4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-urea;4-Amino-N-(4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-butyramide;6-{2-pyridin-3-ylmethylamino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine;3-Amino-N-(4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-propionamide;4-[1,4,7]Triazonan-1-yl-6,7-dihydro-5H-benzo[6,7]cydohepta[1,2-d]pyrimidin-2-ylamine;N,N-Dimethyl-N′-(4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-ethane-1,2-diamine;4-(Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-5,6-dihydro-7-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;4-((R)-3-Methylamino-pyrrolidin-1-yl)-6,7,9,10,11,12-hexahydro-5H-1,3-diaza-benzo[3,4]cyclohepta[1,2-b]naphthalen-2-ylamine;4′(Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6,7,9,10,11,12-hexahydro-5H-1,3-diaza-benzo[3,4]cyclohepta[1,2-Nnaphthalen-2-ylamine;4-Piperazin-1-yl-6,7,9,10,11,12-hexahydro-5H-1,3-diaza-benzo[3,4]cyclohepta[1,2-Nnaphthalen-2-ylamine;9-Iodo-4-({R)-3-methylamino-pyrrolidin-1-yl)-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;9-lodo-4-piperazin-1-yl-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;9-lodo-4-octahydro-pyrrolo[3,4-b]pyridin-6-yl-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;2,4-Di-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine;2-Amino-4-octahydro-pyrrolo[3,4-b]pyridin-6-yl-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cycloheptene-9-carbonitrile;4-Octahydro-pyrrolo[3,4-b]pyridin-6-yl-9-phenyl-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;4-Octahydro-pyrrolo[3,4-b]pyridin-6-yl-9-pyridin-3-yl-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;4-((R)-3-Methylamino-pyrrolidin-1-yl)-6,7-dihydro-5-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;2-Amino-4-octahydro-pyrrolo[3,4-b]pyridin-6-yl-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cycloheptene-9-carboxylicacid methyl ester; 4-Piperazin-1-yl-6,7-dihydro-5-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;4-(Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6,7-dihydro-5-thia-1,3-diaza-dibenzo[a.c]cyclohepten-2-ylamine;4-((R)-3-Methylamino-pyrrolidin-1-yl)-5,5-dioxo-6,7-dihydro-5H-5λ6-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;4-((R)-3-Methylamino-pyrrolidin-1-yl)-5-oxo-6,7-dihydro-5-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;N4-(3-Piperidin-1-yl-propyl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-]pyrimidine-2,4-diamine;4-(4-Dimethylamirro-piperidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;10-fluoro-4-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-amine;4-[1,4]Diazepan-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;(1R,5S)-4-(3,6-Diaza-bicyclo[3.2.0]hept-6-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;4-Piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine;(3aS,6aS)-4-(Hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;{1S,5S)-4-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;N4-Piperidin-3-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,4-diamine;N4-(Octahydro-isoindol-4-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,4-diamine;Methyl-{4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-amine;4-{3-(R)-Methylamino-pyrrolidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine;[1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl)-azetidin-3-yl]-amine;8,10-Dimethyl-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;6-{2-(1H-imidazol-4-yl)ethylamino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine;(2-Amino-4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-10-yl)-methyl-carbannicacid methyl ester;10-N-Methyl-4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,10-diamine;(2-Amino-4-octahydro-pyrrolo[3,4-b]pyridin-6-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-10-yl)-methyl-carbamicacid methyl ester;10-N-methyl-4-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,10-diamine;N-{2-Amino-4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-11-yl)-acetamide;4-(Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2-carboxylicacid methyl ester;4-(Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2-carboxylicacid.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2009137492:4-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl-6,7-dihydro-5H-thieno[2′,3′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;4-[(3R)-3-aminopyrrolidin-1-yl]-6,7-dihydro-5H-thieno[2′, 3′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;4-[(3R)-3-(methylamino)pyrrolidin-l-yl]-6,7-dihydro-5H-thieno[2′,3′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;4-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl-6,7-dihydro-5H-furo[2′,3′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;9-methyl-4-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl-6,7-dihydro-5H-furo[2′,3′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;4-[(3R)-3-aminopyrrolidin-1-yl]-9-methyl-6,7-dihydro-5H-furo[2′,3′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;4-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl-6,7-dihydro-5H-furo[3′,2′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;4-[(3R)-3-aminopyrrolidin-1-yl]-8-methyl-5,6,7,8-tetrahydropyrazolo[3′,4′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;8-tert-butyl-4-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl-5,6,7,8-tetrahydropyrazolo[3′,4′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-8-phenyl-5,6,7,8-tetrahydropyrazolo[3′,4′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;9-bromo-4-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl-6,7-dihydro-5H-thieno[2′,3′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;4-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl-9-phenyl-6,7-dihydro-5H-thieno[2′,3′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;4-[(3R)-3-aminopyrrolidin-1-yl]-6,7-dihydro-5H-pyrido[3′,2′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;4-[(3R)-3-aminopyrrolidin-1-yl]-10-methyl-6,7-dihydro-5H-isoxazolo[5′,4′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;4-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6,7-dihydro-5H-thieno[2′,3′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;or a pharmaceutically acceptable salt thereof.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2009123967:(R)-4-(3-aminopyrrolidin-1-yl)-9,9-dimethyl-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;9,9-dimethyl-4-(piperazin-1-yl)-6,7,89-tetrahydro-5H-cyclohepta[d]pyrimidin-5 2-amine;(R)-4-(3-aminopyrrolidin-1-yl)-9,9-diethyl-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;(R)-4-(3-aminopyrrolidin-1-yl)-9,9-dibenzyl-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;8-phenyl-4-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;8-phenyl-4-(tetrahydro-1H-pyrrolo[3,4-b]pyridine-692H,7H,7aH0-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;4-((R)-3-(methylamino)pyrrolidin-1-yl)-8-phenyl-6,7,8,9-tetrahydro-5H-5-cyclohepta[d]pyrimidin-2-amine;4-(3-aminoazetidin-1-yl)-8-phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;8-phenyl-4-(piperazine-1-yl)-5,6,7,8-tetrahydroquinazolin-2-amine;8-phenyl-4-((4aR,7aR)-tetrahydro-1H-pyrrolo[3,4-b]pyridin-6(2H,7H,7aH)-yl)-5,6,7,8-tetrahydroquinazolin-2-amine;4-((R)-3-(methylamino)pyrrolidin-1-yl)-8-phenyl-5,6,7,8-tetrahydroquinazolin-2-amine;8,8-dimethoxy-4-(piperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-2-amine;4-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;9-(2-methylpyridin-4-yl)-4-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;methyl5-(2-amino-4-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-9-yl)nicotinate;5-(2-amino-4-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-9-yl)nicotinicacid;4-((R)-3-(methylamino)pyrrolidin-1-yl)-9-phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;4-(3-(methylamino)azetidin-1-yl)-9-phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;9-phenyl-4-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;9-phenyl-4-tetrahydro-1H-pyrrolo[3,4-b]pyridine-6(2H,7H,7aH)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;or5,9-phenyl-4-((4aR,7aR)-tetrahydro-1H-pyrrolo[3,4-b]pyridin-6(2H,7H,7aH)-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2005/054239:4-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6-phenylpyrimidin-2-amine;4-(3-methoxyphenyl)-6-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-amine;3-{2-amino-6-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-4-yl}benzonitrile;4-(1-naphthyl)-6-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-amine;4-(3-methylphenyl)-6-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-amine;4-(3-chlorophenyl)-6-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-amine4-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6-[3-(trifluoromethyl)phenyl]pyrimidin-2-amine;1-(3-{2-amino-6-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-4-yl}phenyl)ethanone;4-(3-nitrophenyl)-6-[octahydro-6H-pyrrolo [3,4-b]pyridin-6-yl]pyrimidin-2-amine;(3-{2-amino-6-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidm-4-yl}phenyl)methanol;4-(3,4-dichlorophenyl)-6-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-amine;4-(4-nitrophenyl)-6-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-amine;4-(3-fluorophenyl)-6-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-amine;5-methyl-4-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6-phenylpyrimidin-2-amine;4-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6-(3-thienyl)pyrimidin-2-amine;4-(3-chlorophenyl)-5-methyl-6-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-amine;5-methyl-4-(3-methylphenyl)-6-[octahydro-6H-pyrrolo [3,4-b]pyridin-6-yl]pyrimidin-2-amine;4-(3-fluorophenyl)-5-methyl-6-[octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-amine;4-(3-aminopyrrolidin-1-yl)-6-phenylpyrimidin-2-amine;4-[3-(methylamino)azetidin-1-yl]-6-phenylpyrimidin-2-amine;4-[3-(dimethylamino)azetidin-1-yl]-6-phenylpyrimidin-2-amine;4-(3-chlorophenyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidin-2-amine;4-[3-(methylamino)azetidin-1-yl]-6-(3-methylphenyl) pyrimidin-2-amine;4-(3-fluorophenyl)-6-[3-(methylamino)azetidin-1-yl] pyrimidin-2-amine;4-(3-methoxyphenyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidin-2-amine;3-{2-amino-6-[3-(methylamino)azetidin-1-yl]pyrimidin-4-yl}benzonitrile;1-(3-{2-amino-6-[3-(methylamino)azetidin-1-yl]pyrimidin-4-yl}phenypethanone;4-[3-(methylamino) azetidin-1-yl]-6-(3-nitrophenyl)pyrimidin-2-amine;3-{2-amino-6-[3-(methylamino) azetidin-1-yl]pyrimidin-4-yl}phenol;4-(3-aminophenyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidin-2-amine;5-fluoro-4-[3-(methylamino)azetidin-1-yl]-6-phenylpyrimidin-2-amine;5-methyl-4-[methylamino)azetidin-1-yl]-6-phenylpyrimidin-2-amine;4-[3-(methylamino)azetidin-1-yl]-6-[3-(trifluoromethyl)phenyl]pyrimidin-2-amine;4-[3-(dimethylamino)phenyl]-6-[3-(methylamino)azetidin-1-yl]pyrimidin-2-amine;4-[3-(methylamino)azetidin-1-yl]-6-(1-naphthyl)pyrimidin-2-amine;4-[3-(methylamino)azetidin-1-yl]-6-(4-methylphenyl)pyrimidin-2-amine;4-(4-chlorophenyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidin-2-amine;4-(4-fluorophenyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidin-2-amine;4-(4-methoxyphenyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidin-2-amine;4-{2-amino-6-[3-(methylamino)azetidin-1-yl]pyrimidin-4-yllbenzonitrile;4-[3-(methylamino)azetidin-1-yl]-6-(4-nitrophenyl)pyrimidin-2-amine; and4-{2-amino-6-[3-(methylamino)azetidin-1-yl]pyrimidin-4-yl}phenol;4-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6-phenylpyrimidin-2-aminetrihydrochloride;4-(3-methoxyphenyl)-6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-aminetrihydrochloride;3-{2-amino-6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-4-yl}benzonitriletrihydrochloride;4-(1-naphthyl)-6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-aminetrihydrochloride;4-(3-methylphenyl)-6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-aminetrihydrochloride;4-(3-chlorophenyl)-6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-aminetrihydrochloride;4-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6-[3-(trifluoromethyl)phenyl]pyrimidin-2-aminetrihydrochloride;1-(3-{2-amino-6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-4-yl}phenyl)ethanonetrihydrochloride;4-(3-nitrophenyl)-6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-aminetrihydrochloride;(3-{2-amirio-6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-4-yl}phenyl)methanoltrihydrochloride;4-(3,4-dichlorophenyl)-6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-aminedihydrochloride;4-(4-nitrophenyl)-6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-aminedihydrochloride;4-(3-fluorophenyl)-6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-aminedihydrochloride;5-methyl-4-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6-phenylpyrimidin-2-aminedihydrochloride;4-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6-(3-thienyl)pyrimidin-2-aminedihydrochloride;4-(3-chlorophenyl)-5-methyl-6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-aminedihydrochloride;5-methyl-4-(3-methylphenyl)-6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-aminedihydrochloride; and4-(3-fluorophenyl)-5-methyl-6-[(4aR,7aR)-6ctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-aminedihydrochloride.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2005/014556: 4-(3-aminopyrrolidin-1-yl)-6-phenylpyrimidin-2-aminetrihydrochloride; 4-[3-(dimethylamino)pyrrolidin-1-yl]-6-phenylpyrimidin-2-amine trihydrochloride;4-[3-(methylamino) pyrrolidin-1-yl]-6-phenylpyrimidin-2-aminetrihydrochloride; 4-[3-(methylamino)pyrrolidin-1-yl]-6-(3-nitrophenyl)pyrimidin-2-amine trihydrochloride;4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-6-(3-nitrophenyl)pyrimidin-2-aminetrihydrochloride;4-[(3S)-3-(methylamino)pyrrolidin-1-yl]-6-(3-nitrophenyl)pyrimidin-2-aminetrihydrochloride;4-[(3S)-3-(methylamino)pyrrolidin-1-yl]-6-phenylpyrimidin-2-aminetrihydrochloride; 4-[(3R)-3-(methylamino)pyrrol idin-1-yl]-6-phenylpyrimidin-2-amine trihydrochloride;4-[3-(methylamino)pyrrolidin-1-yl]-6-(3-methylphenyl)pyrimidin-2-aminetrihydrochloride;1-(3-{2-amino-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-yl}phenyl)ethanone trihydrochloride;3-{2-amino-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-yl}phenoltrihydrochloride;(3-{2-amino-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-yl}phenyl)methanoltrihydrochloride; and3-{2-amino-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-yl}benzonitriletrihydrochloride;3-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]phenol;1-{3-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]phenyl}ethanone;{3-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]phenyl}methanol;4-(4-methylpiperazin-1-yl)-6-[3-(trifluoromethyl)phenyl]pyrimidin-2-amine;4-biphenyl-3-yl-6-(4-methylpiperazin-1-yl)pyrimidin-2-aminetrihydrochloride;4-[3-(dimethylamino)phenyl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;4-(4-methylpiperazin-1-yl)-6-(1-naphthyl)pyrimidin-2-amine; and3-[2-amino-6-(4-methylpiperazin-1-yl) pyrimidin-4-yl] benzonitrile.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2006/056848:(5-chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; inWO02/072548:6-bromo-4-methyl-2-{[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]carbonyl}-1H-benzimidazoleand6-fluoro-4-methyl-2-{[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]carbonyl}-1H-benzimidazole.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2007/072163:N⁴-(Cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,N⁴-(Cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diaminetartrate,N⁴-Isobutyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,N⁴-(2,2-Dimethylpropyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine-N-Isobutyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-amine,N-(Cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-amine,N⁴-(2,2-Dimethylpropyl)-6-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine,N⁴-Cyclopropyl-6-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine,N⁴-Cyclobutyl-6-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine,N⁴-(2,2-Dimethylpropyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine,6-(3-Methylamino-azetidin-1-yl)-N⁴-(3,3,3-trifluoro-propyl)-pyrimidine-2,4-diamine,N⁴-Cyclopropylmethyl-6-(3-methylamino-azetidin-1-yl)-pyrimidine-2,4-diamine,N⁴-(3,3-Dimethyl-butyl)-6-(3-methylamino-azetidin-1-yl)-pyrimidine-2,4-diamine,N⁴-(3-Fluoro-benzyl)-6-(3-methylamino-azetidin-1-yl)-pyrimidine-2,4-diamine,N⁴-Cyclopentylmethyl-6-(3-methylamino-azetidin-1-yl)-pyrimidine-2,4-diamine,N⁴-Isobutyl-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine,6-[3-(Methylamino)azetidin-1-yl]-N⁴-propylpyrimidine-2,4-diamine,N⁴-(2-Methoxybenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine,N⁴-(2,2-Dimethylpropyl)-6-[(3R)-3-methylpiperazin-1-yl]pyrimidine-2,4-diamine,N⁴-Ethyl-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine,N⁴-(Cyclopropylmethyl)-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine,6-[3-(Methylamino)azetidin-1-yl]-N⁴-(2-methylbutyl)pyrimidine-2,4-diamine,N⁴-(2,5-Difluorobenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine,N⁴-(2,3-Difluorobenzyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine,N⁴-Butyl-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diamine,6-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N⁴-(2-methylcyclopropyl)pyrimidine-2,4-diamine,N⁴-Isobutyl-6-(4-methyl-1,4-diazepan-1-yl)pyrimidine-2,4-diamine,N⁴-(Cyclopropylmethyl)-6-(3-pyrrolidin-1-ylazetidin-1-yl)pyrimidine-2,4-diamine,N⁴-Bicyclo[1.1.1]pent-1-yl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,6-[3-Methyl-3-(methylamino)azetidin-1-yl]-N⁴-propylpyrimidine-2,4-diamine,N⁴-(2,2-Dimethylpropyl)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyrimidine-2,4-diamine,N⁴-(2,2-Dimethylpropyl)-6-(3-pyrrolidin-1-ylazetidin-1-yl)pyrimidine-2,4-diamine,N4-(2,2-Dimethylpropyl)-6-[3-(isopropylamino)azetidin-1-yl]pyrimidine-2,4-diamine,N4-(tert-Butyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,6-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N⁴-(1-methylcyclopropyl)pyrimidine-2,4-diamine,N⁴-(tert-Butyl)-6-[(4aS*,7aS*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine,N⁴-(2,2-Dimethylpropyl)-6-piperazin-1-ylpyrimidine-2,4-diamine,N⁴-(2,2-Dimethylpropyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidine-2,4-diaminehydrochloride,N⁴-(2,2-Dimethylpropyl)-6-[(3aR*,7aS*)-octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]pyrimidine-2,4-diamine,6-Piperazin-1-yl-N⁴-propylpyrimidine-2,4-diamine,N⁴-(Cyclopropylmethyl)-6-[4aR,7aR]-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine,N⁴-(2,2-Dimethylpropyl)-6-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamineN⁴-(Cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,N⁴-Isopropyl-6-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine,4-[3-(Methylamino)azetidin-1-yl]-6-(4-methylpiperidin-1-yl)pyrimidin-2-amine,N⁴-(Cyclopentylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,N⁴-Cyclobutyl-6-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidine-2,4-diamine,6-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N⁴-propylpyrimidine-2,4-diamine,and, N⁴-Ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyrimidine-2,4-diamine.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2008/074445:4-(4-Methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;8-Chloro-4-(4-methyl-piperazin-1-yl)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(4-Methylpiperazin-1-yl)pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-amine;8-Chloro-4-(4-methylpiperazin-1-yl)[1]benzofuro[3,2-d]pyrimidin-2-amine;8-Chloro-4-[(3S)-3-methylpiperazin-1-yl][1]benzofuro[3,2-d]pyrimidin-2-amine;8-Methoxy-4-piperazin-1-yl[1]benzofuro[3,2-d]pyrimidin-2-amine, bisacetate salt;N⁴-1-Azabicyclo[2.2.2]oct-3-yl-8-chloro[1]benzofuro[3,2-d]pyrimidine-2,4-diamine;4-(3-Aminopyrrolidin-1-yl)-8-methoxy[1]benzofuro[3,2-d]pyrimidin-2-amine;4-(3-Aminopyrrolidin-1-yl)-7-chloro[1]benzofuro[3,2-d]pyrimidin-2-amine;7-Chloro-4-piperazin-1-yl[1]benzofuro[3,2-αf]pyrimidin-2-amine;8-Chloro-4-piperazin-1-yl[1]benzofuro[3,2-d]pyrimidin-2-amine,dihydrochloride;8-(2-Methoxyethoxy)-4-piperazin-1-yl[1]benzofuro[3,2-d]pyrimidin-2-amine;8-Ethoxy-4-piperazin-1-yl[1]benzofuro[3,2-d]pyrimidin-2-amine;8-Chloro-4-(3-ethylpiperazin-1-yl)[1]benzofuro[3,2-d]pyrimidin-2-amine;8-Chloro-4-[(3S)-3-isopropylpiperazin-1-yl][1]benzofuro[3,2-d]pyrimidin-2-amine;8-Chloro-4-piperazin-1-y1][1]benzofuro[3,2-d]pyrimidin-2-amine;8-Chloro-4-(1,4-diazepan-1-yl)[1]benzofuro[3,2-d]pyrimidin-2-amine;8-Chloro-4-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl][1]benzofuro[3,2-d]pyrimidin-2-amine;8-Chloro-[(3S)-3-methyl-1,4-diazepan-1-yl][1]benzofuro[3,2-d]pyrimidin-2-amine;(8-Chloro-N4-[2-(methylamino)ethyl][1]benzofuro[3I2-c0pyrimidine-2,4-diamine;8-Chloro-N⁴-pyrrolidin-3-yl[1]benzofuro[3,2-d]pyrimidine-2,4-diamine(7-Chloro-4-(4-methylpiperazin-1-yl)[1]benzofuro[3,2-d]pyrimidin-2-amine,formate salt;2-Amino-4-(3-aminopyrrolidin-1-yl)[1]benzofuro[3,2-d]pyrimidin-8-ol;4-(4-Methyl-piperazin-1-yl)-5H-indeno[1,2-d]pyrimidin-2-ylamine;8-Chloro-4-(4-methyl-piperazin-1-yl)-5H-indeno[1,2-d]pyrimidin-2-ylamine;8-Bromo-4-[(3S)-3-methylpiperazin-1-yl][1]benzofuro[3,2-d]pyrimidin-2-amine);8-Bromo-4-piperazin-1-yl[1]benzofuro[3,2-d]pyrimidin-2-amine;8-Bromo-4-(1,4-diazepan-1-yl)[1]benzofuro[3,2-d]pyrimidin-2-amine;Methyl-2-amino-4-[(3S)-3-methylpiperazin-1-yl][1]benzofuro[3,2-d]pyrimidine-8-carboxylate;Methyl-2-amino-4-(1,4-diazepan-1-yl)[1]benzofuro[3,2-d]pyrimidine-8-carboxylate;2-Amino-4-[(3S)-3-methylpiperazin-1-yl][1]benzofuro[3,2-d]pyrimidine-8-carboxylicacid; 4-(4-Methylpiperazin-1-yl)[1]benzofuro[3,2-d]pyrimidin-2-amine;8-Chloro-4-(4-methylpiperazin-1-yl)[1]benzofuro[3,2-d]pyrimidin-2-amine;4-(4-Methylpiperazin-1-yl)-5H-indeno[1,2-d]pyrimidin-2-amine;8-Chloro-4-[(3R)-3-methylpiperazin-1-yl][1]benzofuro[3,2-d]pyrimidin-2-amine;4-(3-Aminopyrrolidin-1-yl)-7-chloro[1]benzofuro[3,2-d]pyrimidin-2-amine;7-Chloro-4-piperazin-1-yl[1]benzofuro[3,2-d]pyrimidin-2-amine;7-Chloro-4-(4-methylpiperazin-1-yl)[1]benzofuro[3,2-d]pyrimidin-2-amine,formic acid salt;4-(4-Methylpiperazin-1-yl)pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-2-amine;8-Chloro-4-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl][1]benzofuro[3,2-d]pyrimidin-2-amine;8-Chloro-4-(4-methylpiperazin-1-yl)-5H-indeno[1,2-d]pyrimidin-2-amine;8-Chloro-4-[(3S)-3-methyl-1,4-diazepan-1-yl][1]benzofuro[3,2-d]pyrimidin-2-amine;4-(3-Aminopyrrolidin-1-yl)-8-methoxy[1]benzofuro[3,2-d]pyrimidin-2-amine;8-Chloro-4-piperazin-1-yl[1]benzofuro[3,2-d]pyrimidin-2-amine;2-Amino-4-(3-aminopyrrolidin-1-yl)[1]benzofuro[3,2-d]pyrimidin-8-ol;8-Chloro-N⁴-[2-(methylamino)ethyl][1]benzofuro[3,2-d]pyrimidine-2,4-diamine;8-Chloro-4-(1,4-diazepan-1-yl)[1]benzofuro[3,2-d]pyrimidin-2-amine;8-Methoxy-4-piperazin-1-yl[1]benzofuro[3,2-d]pyrimidin-2-amine,diacetate;8-Chloro-4-[(3S)-3-methylpiperazin-1-yl][1]benzofuro[3,2-d]pyrimidin-2-amine;8-Chloro-4-piperazin-1-yl[1]benzofuro[3,2-d]pyrimidin-2-amine,dihydrochloride;8-Bromo-4-[(3S)-3-methylpiperazin-1-yl][1]benzofuro[3,2-d]pyrimidin-2-amine;8-Bromo-4-piperazin-1-yl[1]benzofuro[3,2-d]pyrimidin-2-amine;8-Bromo-4-(1,4-diazepan-1-yl)[1]benzofuro[3,2-d]pyrimidin-2-amine;Methyl-2-amino-4-[(3S)-3-methylpiperazin-1-yl][1]benzofuro[3,2-d]pyrimidine-8-carboxylate;Methyl-2-amino-4-(1,4-diazepan-1-yl)[1]benzofuro[3,2-d]pyrimidine-8-carboxylate;2-Amino-4-[(3S)-3-methylpiperazin-1-yl][1]benzofuro[3,2-d]pyrimidine-8-carboxylicacid; 8-Ethoxy-4-piperazin-1-yl[1]benzofuro[3,2-d]pyrimidin-2-amine;8-Chloro-4-[(3S)-3-methyl-1,4-diazepan-1-yl][1]benzofuro[3,2-d]pyrimidin-2-amine;4-(3-Aminopyrrolidin-1-yl)-8-methoxy[1]benzofuro[3,2-d]pyrimidin-2-amine;8-Chloro-4-piperazin-1-yl[1]benzofuro[3,2-d]pyrimidin-2-amine;2-Amino-4-(3-aminopyrrolidin-1-yl)[1]benzofuro[3,2-d]pyrimidin-8-ol;8-Chloro-N⁴-[2-(methylamino)ethyl][1]benzofurol[3,2-d]pyrimidine-2,4-diamine;8-Chloro-4-(1,4-diazepan-1-yl)[1]benzofuro[3,2-d]pyrimidin-2-amine;8-Methoxy-4-piperazin-1-yl[1]benzofuro[3,2-d]pyrimidin-2-amine,diacetate;8-Chloro-4-[(3S)-3-methylpiperazin-1-yl][1]benzofuro[3,2-d]pyrimidin-2-amine;8-Chloro-4-piperazin-1-yl[1]benzofuro[3,2-cy]pyrimidin-2-amine,dihydrochloride;8-Bromo-4-[(3S)-3-methylpiperazin-1-yl][1]benzofuro[3,2-d]pyrimidin-2-amine;8-Bromo-4-piperazin-1-yl[1]benzofuro[3,2-d]pyrimidin-2-amine;8-Bromo-4-(1,4-diazepan-1-yl)[1]benzofuro[3,2-d]pyrimidin-2-amine.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2008/031556:4-(4-methylpiperazin-1-yl)-6-piperidin-1-ylpyrimidin-2-amine;4-(1,3-dihydro-2H-isoindol-2-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;4-(4-methylpiperazin-1-yl)-6-(4-methylpiperidin-1-yl)pyrimidin-2-amine;4-[4-(2-methoxyphenyl)piperidin-1-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;4-(3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;4-(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;4-(3-aminopyrrolidin-1-yl)-6-(1,3-dihydro-2H-isoindol-2-yl)pyrimidin-2-amine;4-(4-methylpiperazin-1-yl)-6-(2-methylpyrrolidin-1-yl)pyrimidin-2-amine;4-(2-ethylpiperidin-1-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;4-[3-(2-methoxyphenyl)pyrrolidin-1-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;4-[3-(4-chlorophenyl)pyrrolidin-1-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;4-(2-methylpyrrolidin-1-yl)-6-piperazin-1-ylpyrimidin-2-amine;4-(4-methylpiperazin-1-yl)-6-[(2R)-2-methylpyrrolidin-1-yl]pyrimidin-2-amine;4-(4-methylpiperazin-1-yl)-6-[(2S)-2-methylpyrrolidin-1-yl]pyrimidin-2-amine;4-(2,6-dimethylpiperidin-1-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;4-(6-azabicyclo[3.2.1]oct-6-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;4-azepan-1-yl-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;1-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-4-(4-chlorophenyl)piperidin-4-ol;4-(4-methylpiperazin-1-yl)-6-(3-phenylpiperidin-1-yl)pyrimidin-2-amine;N⁴-cyclohexyl-6-(hexahydropyrrolo[1,2-a]pyrazin-2m(1H)-yl)pyrimidine-2,4-diamine;N⁴-adamantan-1-yl-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine;6-(4-methylpiperazin-1-yl)-N⁴-(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)pyrimidine-2,4-diamine;N⁴-adamantan-2-yl-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine;6-(4-methylpiperazin-1-yl)-N⁴(1R;4R)(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)pyrimidine-2,4-diamine;N⁴-cyclohexyl-N⁴-methyl-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-cliamine;4-(7-azabicyclo[2.2.1]hept-7-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;4-(3-aminopyrrolidin-1-yl)-6-(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)pyrimidin-2-amine;4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-6-(2-methylpyrrolidin-1-yl)pyrimidin-2-amine;N⁴-1-azabicyclo[2.2.2]oct-3-yl-6-(1,3-dihydro-2H-isoindol-2-yl)pyrimidine-2,4-diamine;4-(3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;N⁴-1-azabicyclo[2.2.2]oct-3-yl-6-(2-methylpyrrolidin-1-yl)pyrimidine-2,4-diamine;6-(2-methylpyrrolidin-1-yl)-N⁴-pyrrolidin-3-ylpyrimidine-2,4-diamine;4-[4-(methylamino)piperidin-1-yl]-6-(2-methylpyrrolidin-1-yl)pyrimidin-2-amine;4-(1,3-dihydro-2H-isoindol-2-yl)-6-[4-(methylamino)piperidin-1-yl]pyrimidin-2-amine;4-(1,3-dihydro-2H-isoindol-2-yl)-6-(4-methyl-1,4-diazepan-1-yl)pyrimidin-2-amine;6-[(3R)-3-aminopyrrolidin-1-yl]-N⁴-cyclohexylpyrimidine-2,4-diaminetriacetate salt;4(R)-(3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine4(S)-(3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;N⁴-cyclohexyl-N⁶-[2-(dimethylamino)ethyl]pyrimidine-2,4,6-triamine;N4-cyclohexyl-6-[4-(methylamino)piperidin-1-yl]pyrimidine-2,4-diamine;6-[(3S)-3-aminopyrrolidin-1-yl]-N⁴-cyclohexylpyrimidine-2,4-diamine;N⁴-cyclopentyl-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine;N⁴-cyclopentyl-N4-methyl-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine;N⁴-cycloheptyl-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine;4-[(1R*,5S*)-8-azabicyclo[3.2.1]oct-8-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;N⁴-[(1R*,2S*,4S*)-bicyclo[2.2.1]hept-2-yl]-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine;N⁴-bicyclo[2.2.1]hept-2-yl-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine;N⁴-[(1R*,2S*,4S*)-bicyclo[2.2.1]hept-2-yl]-N⁶-dimethylaminoJethyllpyrimidine-2,4-triamine;N⁴-[(1R*,2S*,4S*)-bicyclo[2.2.1]hept-2-yl]-6-[(3aR*,6aS*)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]pyrimidine-2,4-diamine;4-cyclohexyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;4-adamantan-2-yl-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;4-Isopropyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;4-(1-methylpentyl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;4-cyclopentyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;4-(1-ethylpropyl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;4-cyclohexyl-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-2-amine;4-cyclohexyl-6-(4-methyl-1,4-diazepan-1-yl)pyrimidin-2-amine;4-cyclohexyl-6-(4-ethylpiperazin-1-yl)pyrimidin-2-amine;4-cyclohexyl-6-[3-(dimethylamino)pyrrolidin-1-yl]pyrimidin-2-amine;6-cyclohexyl-N⁴-methyl-N⁴-(1-methylpyrrolidin-3-yl)pyrimidine-2,4-diamine;6-cyclohexyl-N⁴-(1-methylpiperidin-4-yl)pyrimidine-2,4-diamine;4(R)-(4-methylpiperazin-1-yl)-6-(1-phenylethyl)pyrimidin-2-amine;4(S)-(4-methylpiperazin-1-yl)-6-(1-phenylethyl)pyrimidin-2-amine;4-(3-aminopyrrolidin-1-yl)-6-cyclopropylpyrimidin-2-amine;4-cyclopropyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine;4-(3-aminopyrrolidin-1-yl)-6-(4-methylcyclohex-1-en-1-yl)pyrimidin-2-aminedi-trifluoroacetic acid salt ;6-cyclohex-1-en-1-yl-N⁴-[2-(dimethylamino)ethyl]pyrimidine-2,4-diamine;4-tert-butyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine acetate salt;4-tert-butyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine acetatesalt;4-[adamantan-2-yl]-6-[(3S)-3-aminopyrrolidin-1-yl]pyrimidin-2-amine;4-[adamantan-2-yl]-6-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine;4-cyclohept-1-en-1-yl-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine;4-cyclopentyl-6-(3-methylpiperazin-1-yl)pyrimidin-2-amine;4-(3-aminoazetidin-1-yl)-6-cyclohex-1-en-1-ylpyrimidin-2-amine;4-cyclohexyl-6-(3-methylpiperazin-1-yl)pyrimidin-2-amine;4-(3-aminoazetidin-1-yl)-6-cyclohexylpyrimidin-2-amine;4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydronaphthalen-2-yl)pyrimidin-2-amine;4-[3-(methylamino)pyrrolidin-1-yl]-6-(1,2,3,4-tetrahydronaphthalen-2-yl)pyrimidin-2-amine;4-(3-aminopyrrolidin-1-yl)-6-(1,2,3,4-tetrahydronaphthalen-2-yl)pyrimidin-2-amine;4-cyclopentyl-6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-2-amine;4-cyclopentyl-6-[(3R)-3-methylpiperazin-1-yl]pyrimidin-2-amine;4-cyclohexyl-6-[(2S)-2-methylpiperazin-1-yl]pyrimidin-2-amine;4-[(3R)-3-aminopyrrolidin-1-yl]-6-[(1E)-3,3-dimethylbut-1-en-1-yl]pyrimidin-2-amine4-[3-(aminomethyl)azetidin-1-yl]-6-cyclohexylpyrimidin-2-amine;4-(3-aminoazetidin-1-yl)-6-cyclopentylpyrimidin-2-amine;4-cyclopentyl-6-(3-ethylpiperazin-1-yl)pyrimidin-2-amine;4-cyclopentyl-6-[(3S)-3-isopropylpiperazin-1-yl]pyrimidin-2-amine;4-cyclopentyl-6-(3,8-diazabicyclo[3.2.1]oct-3-yl)pyrimidin-2-amine;N⁴-(2,3-dihydro-1H-inden-2-yl)-6-[3-methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine;4-cyclopentyl-6-[(3S)-3-isobutylpiperazin-1-yl]pyrimidin-2-amine;4-cyclopentyl-6-[3-(ethylamino)azetidin-1-yl]pyrimidin-2-amine;6-(4-methylpiperazin-1-yl)-N⁴-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4-diamine;6-(4-methylpiperazin-1-yl)-N⁴-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4-diamineacetate; N⁴-cyclohexyl-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine;4-(1,3-dihydro-2H-isoindol-2-yl)-6-piperazin-1-ylpyrimidin-2-amine;4-(3-aminopyrrolidin-1-yl)-6-(2-methylpyrrolidin-1-yl)pyrimidin-2-amine;4-[3-(methylamino)pyrrolidin-1-yl]-6-(2-methylpyrrolidin-1-yl)pyrimidin-2-amine;6-(3-aminopyrrolidin-1-yl)-N⁴-[(1R*,2S*,4S*)-bicyclo[2.2.1]hept-2-yl]pyrimidine-2,4-diamine;N⁴-[(1R*,2S*,4S*)-bicyclo[2.2.1]hept-2-yl]-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine;6-[(3S)-3-aminopyrrolidin-1-yl]-N⁴-[(1R*,2S*,4S*)-bicyclo[2.2.1]hept-2-yl]pyrimidine-2,4-diamine;6-[(3R)-3-aminopyrrolidin-1-yl]-N⁴-[(1R*,2S*,4S*)-bicyclo[2.2.1]hept-2-yl]pyrimidine-2,4-diamine;6-[(3S)-3-aminopyrrolidin-1-yl]-N⁴-[(1R*,2R*,4S*)-bicyclo[2.2.1]hept-2-yl]pyrimidirre-2,4-diamine;6-[(3R)-3-aminopyrrolidin-1-yl]-N⁴-[(1R*,2R*,4S*)-bicyclo[2.2.1]hept-2-yl]pyrimidine-2,4-diamine;N4-[exo-bicyclo[2.2.1]hept-2-yl]-6-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine;N⁴-[(1R*,2S*,4S*)-bicyclo[2.2.1]hept-2-yl]-6-[3R]-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine;N⁴-[(1R*,2S*,4S*)-bicyclo[2.2.1]hept-2-yl]-6-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine;N⁴-[(1R*,2S*,4S*)-bicyclo[2.2.1]hept-2-yl]-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine;N⁴-[(1R*,2S*,4S*)-bicyclo[2.2.1]hept-2-yl]-6-(3-methylpiperazin-1-y)pyrimidine-2,4-diamine;N⁴-[(1R*,2R*,4S*)-bicyclo[2.2.1]hept-2-yl]-6-(1,4-diazepan-1-yl)pyrimidine-2,4-diamine;N⁴-[(1R*,2R*,4S*)-bicyclo[2.2.1]hept-2-yl]-6-((4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)pyrimidine-2,4-diamine;N⁴-[(1R*,2R*,4S*)-bicyclo[2.2.1]hept-2-yl]-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyrimidine-2,4-diamine;N⁴-[(1R*,2R*,4S*)-bicyclo[2.2.1]hept-2-yl]-6-piperazin-1-yl-pyrimidine-2,4-diamine;4-(3-aminopyrrolidin-1-yl)-6-cyclopentylpyrimidin-2-amine;4-adamantan-2-yl-6-(3-aminopyrrolidin-1-yl)pyrimidin-2-amine;4-cyclopentyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine;4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyclohexylpyrimidin-2-amine;4-[(3R)-3-aminopyrrolidin-1-yl]-6-cyclohexylpyrimidin-2-amine;4-(3-aminopyrrolidin-1-yl)-6-(cyclohexylmethyl)pyrimidin-2-amine;4-cyclopentyl-6-piperazin-1-ylpyrimidin-2-amine;4-[adamantan-2-yl]-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine;4-[adamantan-2-yl]-6-[(3R)-3-aminopyrrolidin-1-yl]pyrimidin-2-amine;4-(cyclopentylmethyl)-6-(3-methylpiperazin-1-yl)pyrimidin-2-amine;4-(3-aminopyrrolidin-1-yl)-6-(cyclopentylmethyl)pyrimidin-2-amine;4-cyclohexyl-6-[3-(methylamino)azetidin-1-yl]pyrimidin-2-amine;4-cyclopentyl-6-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-amine;4-cyclohexyl-6-(1,4-diazepan-1-yl)pyrimidin-2-amine;4-cyclopentyl-6-(1,4-diazepan-1-yl)pyrimidin-2-amine;6-cyclopentyl-N⁴-[2-(methylamino)ethyl]pyrimidine-2,4-diamine;4-[(3R)-3-aminopyrrolidin-1-yl]-6-cyclohex-1-en-1-ylpyrimidin-2-amine;N⁴-cyclohexyl-6-(4-methylpiperazin-1-yl)pyrimidine-2,4-diamine;4-(1,3-dihydro-2H-isoindol-2-yl)-6-piperazin-1-ylpyrimidin-2-amine;4-(3-aminopyrrolidin-1-yl)-6-(2-methylpyrrolidin-1-yl)pyrimidin-2-amine;4-[3-(methylamino)pyrrolidin-1-yl]-6-(2-methylpyrrolidin-1-yl)pyrimidin-2-amine;6-(3-aminopyrrolidin-1-yl)-N⁴-[(1R*,2S*,4S*)-bicyclo[2.2.1]hept-2-yl]pyrimidine-2,4-diamine;N4-[(1R*,2S*,4S*)-bicyclo[2.2.1]hept-2-yl]-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine;6-[(3S)-3-aminopyrrolidin-1-yl]-N⁴-[(1R*,2S*,4S*)-bicyclo[2.2.1]hept-2-yl]pyrimidine-2,4-diamine;6-[(3R)-3-aminopyrrolidin-1-yl]-N⁴-[(1R*,2S*,4S*)-bicyclo[2.2.1]hept-2-yl]pyrimidine-2,4-diamine;6-[(3S)-3-aminopyrrolidin-1-yl]-N⁴-[(1R*,2R*,4S*)-bicyclo[2.2.1]hept-2-yl]pyrimidine-2,4-diamine;6-[(3R)-3-aminopyrrolidin-1-yl]-N⁴-[(1R*,2R*,4S*)-bicyclo[2.2.1]hept-2-yl]pyrimidine-2,4-diamine;N⁴-[exo-bicyclo[2.2.1]hept-2-yl]-6-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine;N⁴-[(1R*,2R*,4S*)-bicyclo[2.2.1]hept-2-yl]-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine;N⁴-[(1R*,2S*,4S*)-bicyclo[2.2.1]hept-2-yl]-6-[(3S)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine;N⁴-[(1R,2S*,4S*)-bicyclo[2.2.1]hept-2-yl]-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine;N⁴-[(1R*,2R*,4S*)-bicyclo[2.2.1]hept-2-yl]-6-(3-methylpiperazin-1-yl)pyrimidine-2,4-diamine;N⁴-[(1R*,2R*,4S*)-bicyclo[2.2.1]hept-2-yl]-6-(1,4-diazepan-1-yl)pyrimidine-2,4-diamine;N⁴-[(1R*,2R*,4S*)-bicyclo[2.2.1]hept-2-yl]-6[((4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)pyrimidine-2,4-diamine;N⁴-[(1R*,2R*,4S*)-bicyclo[2.2.1]hept-2-yl]-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyrimidine-2,4-diamine;N⁴-[(1R*,2R*,4S*)-bicyclo[2.2.1]hept-2-yl]-6-piperazin-1-ylpyrimidine-2,4-diamine;4-(3-aminopyrrolidin-1-yl)-6-cyclopentylpyrimidin-2-amine;4-adamantan-2-yl-6-(3-aminopyrrolidin-1-yl)pyrimidin-2-amine;4-cyclopentyl-6-[3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine;4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyclohexylpyrimidin-2-amine;4-[(3R)-3-aminopyrrolidin-1-yl]-6-cyclohexylpyrimidin-2-amine;4-(3-aminopyrrolid in-1-yl)-6-(cyclohexylmethyl)pyrimidin-2-amine;4-cyclopentyl-6-piperazin-1-ylpyrimidin-2-amine;4-[adamantan-2-yl]-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2-amine;4-[adamantan-2-yl]-6-[(3R)-3-aminopyrrolidin-1-yl]pyrimidin-2-amine;4-(cyclopentylmethyl)-6-(3-methylpiperazin-1-yl)pyrimidin-2-amine;4-(3-aminopyrrolidin-1-yl)-6-(cyclopentylmethyl)pyrimidin-2-amine;4-cyclohexyl-6-[3-(methylamino)azetidin-1-yl]pyrimidin-2-amine;4-cyclopentyl-6-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2-amine;4-cyclohexyl-6-(1,4-diazepan-1-yl)pyrimidin-2-amine;4-cyclopentyl-6-(1,4-diazepan-1-yl)pyrimidin-2-amine;6-cyclopentyl-N⁴-(methylamino)ethyl]pyrimidine-2,4-diamine;4-[(3R)-3-aminopyrrolidin-1-yl]-6-cyclohex-1-en-1-ylpyrimidin-2-amine.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2008122378:6-cyclohex-1-en-1-yl-4-[3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;6-(4-chlorophenyl)-4-(4-methylpiperazin-1-yl)pyridin-2-amine;6-(4-methylcyclohex-1-en-1-yl)-4-(4-methylpiperazin-1-yl)pyridin-2-amine;6-adamantan-2-yl-4-(4-methylpiperazin-1-yl)pyridin-2-amine;4-(3-aminopyrrolidin-1-yl)-6-cyclohex-1-en-1-ylpyridin-2-amine;6-(3-methylphenyl)-4-(4-methylpiperazin-1-yl)pyridin-2-amine;4-[(3R)-3-aminopyrrolidin-1-yl]-6-(4-chlorophenyl)pyridin-2-amine;4-(4-methylpiperazin-1-yl)-6-(4-methylpiperidin-1-yl)pyridin-2-amine;N-cycloheptyl-4-(4-methylpiperazin-1-yl)pyridine-2,6-diamine;4-[3-(methylamino)pyrrolidin-1-yl]-6-(2-methylpyrrolidin-1-yl)pyridin-2-amine;4-(4-methylpiperazin-1-yl)-6-(2-methylpyrrolidin-1-yl)pyridin-2-amine;4-[3-(methylamino)pyrrolidin-1-yl]-6-(4-methylpiperidin-1-yl)pyridin-2-amine;4-[(3-methylamino)pyrrolidin-1-yl]-6-(4-trifluoromethylphenyl)pyridin-2-amine;4-[(3-methylamino)pyrrolidin-1-yl]-6-(4-trifluoromethoxyphenyl)pyridin-2-amine;6-(4-chlorophenyl)-4-[(3-methylamino)pyrrolidin-1-yl)pyridin-2-amine;4-[(3-methylamino)pyrrolidin-1-yl]-6-(3-methylphenyl)pyridin-2-amine;N-cycloheptyl-4-(4-methylpiperazin-1-yl)pyridine-2,6-diamine;4-[3-(methylamino)pyrrolidin-1-yl]-6-(2-methylpyrrolidin-1-yl)pyridin-2-amine;4-[(3-methylamino)pyrrolidin-1-yl]-6-(3-methylphenyl)pyridin-2-amine;6-cyclohex-1-en-1-yl-4-[3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine;6-(4-chlorophenyl)-4-[(3-methylamino)pyrrolidin-1-yl)pyridin-2-amine.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2009047255:4-(4-methylpiperazin-1-yl)-7-phenyl-5,6,7,8-tetrahydroquinazolin-2-amine;4-(3-aminoazetidin-1-yl)-7-phenyl-5,6,7,8-tetrahydroquinazolin-2-amine;4-(3-aminopyrrolidin-1-yl)-7-phenyl-5,6,7,8-tetrahydroquinazolin-2-amine;4-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-7-phenyl-5,6,7,8-tetrahydroquinazolin-2-amine;4-(3-methylpiperazin-1-yl)-7-phenyl-5,6,7,8-tetrahydroquinazolin-2-amine;7-(3-chlorophenyl)-4-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-2-amine;7-(3-chlorophenyl)-4-(1,4-diazepan-1-yl)-5,6,7,8-tetrahydroquinazolin-2-amine;7-(3-chlorophenyl)-4-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-5,6,7,8-tetrahydroquinazolin-2-amine;7,7-dimethyl-4-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-2-amine;4-(1,4-diazepan-1-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinazolin-2-amine;4-(3-aminopyrrolidin-1-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinazolin-2-amine;7,7-dimethyl-4-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-5,6,7,8-tetrahydroquinazolin-2-amine;4-(3-aminopyrrolidin-1-yl)-7-(3-chlorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine;7,7-dimethyl-4-(3-methylpiperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-2-amine;7,7-dimethyl-4-piperazin-1-yl-5,6,7,8-tetrahydroquinazolin-2-amine;7-(2-chlorophenyl)-4-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-2-amine;7-(2-chlorophenyl)-4-(1,4-diazepan-1-yl)-5,6,7,8-tetrahydroquinazolin-2-amine;4-(3-aminopyrrolidin-1-yl)-7-(2-chlorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine;4-(1,4-diazepan-1-yl)-7-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine;7-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-2-amine;4-piperazin-1-yl-7-pyridin-2-yl-5,6,7,8-tetrahydroquinazolin-2-amine;4-(4-methylpiperazin-1-yl)-7-pyridin-2-yl-5,6,7,8-tetrahydroquinazolin-2-amine;4-(1,4-diazepan-1-yl)-7-pyridin-2-yl-5,6,7,8-tetrahydroquinazolin-2-amine;7-(5-chloro-2-thienyl)-4-piperazin-1-yl-5,6,7,8-tetrahydroquinazolin-2-amine;5-(5-chloro-2-thienyl)-4-piperazin-1-yl-5,6,7,8-tetrahydroquinazolin-2-amine;5-(5-chloro-2-thienyl)-4-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-2-amine;7-(5-chloro-2-thienyl)-4-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-2-amine;5-(5-chloro-2-thienyl)-4-(1,4-diazepan-1-yl)-5,6,7,8-tetrahydroquinazolin-2-amine;7-(5-chloro-2-thienyl)-4-(1,4-diazepan-1-yl)-5,6,7,8-tetrahydroquinazolin-2-amine;7-(4-fluorophenyl)-4-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-5,6,7,8-tetrahydroquinazolin-2-aminetrifluoroacetic acid salt;7-(4-fluorophenyl)-N-4-[2-(methylamino)ethyl]-5,6,7,8-tetrahydroquinazoline-2,4-diamine;7,7-dimethyl-N-4-[2-(methylamino)ethyl]-5,6,7,8-tetrahydroquinazoline-2,4-diamine;4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinazolin-2-amine;7,7-dimethyl-4-[(3S)-3-methyl-1,4-diazepan-1-yl]-5,6,7,8-tetrahydroquinazolin-2-amine;8,8-dimethyl-4-(3-methylpiperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-2-amine;4-(3-aminoazetidin-1-yl)-8,8-dimethyl-5,6,7,8-tetrahydroquinazolin-2-amine;8,8-dimethyl-N-4-piperidin-4-yl-5,6,7,8-tetrahydroquinazoline-2,4-diamine;8,8-dimethyl-N-4-pyrrolidin-3-yl-5,6,7,8-tetrahydroquinazoline-2,4-diamine;8,8-dimethyl-4-[(3S)-3-methylpiperazin-1-yl]-5,6,7,8-tetrahydroquinazolin-2-amine;6,6-dimethyl-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine;4-(4-methylpiperazin-1-yl)-7-[4-(trifluoromethyl)pyrimidin-2-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine;7,7-dimethyl-4-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-2-amine;4-(1,4-diazepan-1-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinazolin-2-amine;4-(3-aminopyrrolidin-1-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinazolin-2-amine;7,7-dimethyl-4-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-5,6,7,8-tetrahydroquinazolin-2-amine;7,7-dimethyl-4-(3-methylpiperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-2-amine;7,7-dimethyl-4-piperazin-1-yl-5,6,7,8-tetrahydroquinazolin-2-amine;7-(5-chloro-2-thienyl)-4-piperazin-1-yl-5,6,7,8-tetrahydroquinazolin-2-amine;7-(5-chloro-2-thienyl)-4-(1,4-diazepan-1-yl)-5,6,7,8-tetrahydroquinazolin-2-amine;4-(3-aminoazetidin-1-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinazolin-2-amine;7-isobutyl-4-piperazin-1-yl-5,6,7,8-tetrahydroquinazolin-2-amine;8,8-dimethyl-4-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-2-amine;4-(1,4-diazepan-1-yl)-8,8-dimethyl-5,6,7,8-tetrahydroquinazolin-2-aminebis acetic acid salt;7,7-dimethyl-4-[methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydroquinazolin-2-amine;7,7-dimethyl-4-[(3S)-3-methylpiperazin-1-yl]-5,6,7,8-tetrahydroquinazolin-2-amine;4-(1,4-diazepan-1-yl)-7-isobutyl-5,6,7,8-tetrahydroquinazolin-2-amineacetic acid salt;7-isobutyl-4-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-2-amineacetic acid salt;7,7-dimethyl-4-[methylamino)azetidin-1-yl]-5,6,7,8-tetrahydroquinazolin-2-amine;8,8-dimethyl-4-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-5,6,7,8-tetrahydroquinazolin-2-amine;4′-(4-methylpiperazin-1-yl)-5′,8′-dihydro-6′H-spiro[cyclohexane-1,7′-quinazolin]-2′-amine;4′-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-5′,8′-dihydro-6′H-spiro[cyclohexane-1,7′-quinazolin]-2′-amine;4′-[(3S)-3-methylpiperazin-1-yl]-5′,8′-dihydro-6′H-spiro[cyclohexane-1,7′-quinazolin]-2′-aminebis acetic acid salt;4′-(1,4-diazepan-1-yl)-5′,8′-dihydro-6′H-spiro[cyclohexane-1,7′-quinazolin]-2′-aminebis acetic acid salt;4′-piperazin-1-yl-5′,8′-dihydro-6′H-spiro[cyclohexane-1,7′-quinazolin]-2′-aminebis acetic acid salt;4′-[3-(methylamino)azetidin-1-yl]-5′,8′-dihydro-6′H-spiro[cyclohexane-1,7′-quinazolin]-2′-aminebis acetate salt;4-(3-aminopyrrolidin-1-yl)-7-isobutyl-5,6,7,8-tetrahydroquinazolin-2-aminebis acetate salt;7-isopropyl-4-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydroquinazolin-2-amine;7-isopropyl-4-[(3S)-3-methylpiperazin-1-yl]-5,6,7,8-tetrahydroquinazolin-2-aminebis acetic acid salt;7-isopropyl-4-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-5,6,7,8-tetrahydroquinazolin-2-amine;7-isopropyl-4-[methylamino)azetidin-1-yl]-5,6,7,8-tetrahydroquinazolin-2-amine;tert-butyl-4-(2-amino-7,7-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-1,4-diazepane-1-carboxylate.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2008/003702 : 4-amino-6-chloro-2-(4-methylpiperazinyl)-quinazoline,2-(4-methylpiperazinyl)-4-phenoxyquinazoline,4-(benzyloxy)-2-(4-methylpiperazinyl)-quinazoline,2-(4-methylpiperazinyl)-quinoline, 2-(4-methylpiperazinyl)-quinoxaline,6-chloro-2-(4-methyl-piperazinyl)-quinoline,6-chloro-2-(4-methylpiperazinyl)-quinoxaline,2-(4-methylpiperazinyl)-quinazoline,3-(4-methylpiperazinyl)-isoquinoline,1-(4-methylpiperazinyl)-isoquinoline,3-benzyl-2-(4-methylpiperazinyl)-quinoxaline,6,7-dichloro-2-methoxy-3-(4-methylpiperazinyl)-quinoxaline and7-chloro-2-methoxy-3-(4-methylpiperazinyl)-quinoxaline.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2006/050965:8-chloro-2-methyl-4-(4-methylpiperazin-1-yl)benzo[4,5]furo[3,2-d]pyrimidine;8-chloro-4-(4-methylpiperazin-1-yl)benzo[4,5]furo[3,2-d]pyrimidine;4-(4-methylpiperazin-1-yl)benzo[4,5]furo[3,2-d]pyrimidine;6-chloro-1-(4-methylpiperazin-1-yl)-9H-2,4,9-triazafluorene;4-(Piperazin-1-yl)benzo[4,5]furo[3,2-d]pyrimidine;4-(piperazin-1-yl)benzo[4,5]thieno[3,2-d]pyrimidine;8-Chloro-4-(1,4-diazepan-1-yl)benzo[4,5]thieno[3,2-d]pyrimidine;8-Chloro-2-cyclopropyl-4-(4-methylpiperazin-1-yl)benzo[4,5]furo[3,2-d]pyrimidine;8-Chloro-4-(4-methylpiperazin-1-yl)-2-trifluoromethylbenzo[4,5]furo[3,2-d]pyrimidine;8-Chloro-4-(1-methylpiperidin-4-yl)benzo[4,5]furo[3,2-d]pyrimidine;8-Chloro-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]benzo[4,5]furo[3,2-d]pyrimidine;8-Chloro-4-(3-methylpiperazin-1-yl)benzo[4,5]furo[3,2-d]pyrimidine;8-Chloro-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]benzo[4,5]furo[3,2-d]pyrimidine;8-Chloro-4-(3,4-dimethylpiperazin-1-yl)benzo[4,5]furo[3,2-d]pyrimidine;8-Cloro-4-(1-metylpyrrolidin-3-yl)benzo[4,5]furo[3,2-d]pyrimidine;8-Chloro-4-(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)benzo[4,5]furo[3,2-d]pyrimidine;8-Chloro-4-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]benzo[4,5]furo[3,2-d]pyrimidine;8-Chloro-4-[5-methyl-2,5-diazabicyclo[2.2.2]oct-2-yl]benzo[4,5]furo[3,2-d]pyrimidine;and8-Chloro-4-[5-methyl-2,5-diazabicyclo[3.2.1]oct-2-yl]benzo[4,5]furo[3,2-d]pyrimidine.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2005/014579:4-(1H-Imidazol-4-ylmethoxy)-1-(1-oxo-3-phenylbutyl)-piperidine;4-(1H-Imidazol-4-ylmethoxy)-1-[[4-(trifluoromethyl)phenyl]acetyl]-piperidine;1-[2-(4-Hydroxyphenyl)-1-oxopropyl]-4-[(5-methyl-1H-imidazol-4-yl)methoxy]-piperidine;1-[(4-fluorophenyl)acetyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(2-chlorophenyl)acetyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(4-chlorophenyl)acetyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;4-(H-imidazol-4-ylmethoxy)-1-(phenylacetyl)-piperidine;1-(4-cyclohexylbenzoyl)-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(3,4-dichlorophenyl) acetyl]-4-(H-imidazol-4-ylmethoxy)-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[(4-methylphenyl)acetyl]-piperidine;1-[(3,4-difluorophenyl)acetyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(2,4-difluorophenyl)acetyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[(4′-propyl[1,1′-biphenyl]-4-yl)carbonyl]-piperine;1-[2-(4-hydroxyphenyl)-1-oxopropyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(2E)-3-(3,4-dichlorophenyl)-1-oxo-2-propenyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[3-(2,4-dichlorophenyl)-1-oxopropyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(2,4-dichlorophenyl)acetyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(2-Bromophenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(3-Bromo-2-thienyl)methyl]-4-[(5-methyl-1H-imidazol-4-yl)methoxy]-piperidine;1-[(3-bromo-2-thienyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(4-ethynylphenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[[3-(4-methylphenoxy)phenyl]methyl]-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[[4-(2-propenyloxy)phenyl]methyl]-piperidine;4-[[4-(1H-imidazol-4-ylmethoxy)-1-piperidinyl]methyl]-phenol;4-(1H-imidazol-4-ylmethoxy)-1-[(2-methoxyphenyl)methyl]-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[[3-(4-methoxyphenoxy)phenyl]methyl]-piperidine;1-[(2,3-dichlorophenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(2-chloro-4-fluorophenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-(2-dibenzofuranylmethyl)-4-(1H-imidazol-4-ylmethoxy)-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[[2-(methylthio)phenyl]methyl]-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-(thieno [2,3-b] [I]benzothien-2-ylmethyl)-piperidine;1-[(2-chloro-5-nitrophenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1H-pyrrole,2-[[4-(1H-imidazol-4-ylmethoxy)-1-piperidinyl]methyl]-1-[(4-methylphenyl)sulfonyl]-;2-ethoxy-6-[[4-(1H-imidazol-4-ylmethoxy)-1-piperidinyl]methyl]-phenol;1-(1,3-benzoidoxol-5-ylmethyl)-4-(1H-imidazol-4-ylmethoxy)-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[[4-(phenylmethoxy)phenyl]methyl]-piperidine;1-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(4-bromophenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[(4-methylphenyl)methyl]-piperidine;4-(H-imidazol-4-ylmethoxy)-1-(2-thienylmethyl)-piperidine;1-[(4-chlorophenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(2-chloro-6-fluorophenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[(3-methyl-2-thienyl)methyl]-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-(2-naphthalenylmethyl)-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-(1-naphthalenylmethyl)-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[(2-nitrophenyl) methyl]-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-(3-thienylmethyl)-piperidine;I-([1,1′-biphenyl]-4-ylmethyl)-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(2,5-difluorophenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[(3-phenoxyphenyl)methyl]-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[(3-methylphenyl)methyl]-piperidine;1-(2-furanylmethyl)-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(2,6-dichlorophenyl) methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(4-fluorophenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(3-fluorophenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-(3-furanylmethyl)-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(4-ethylphenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[(2-methylphenyl)methyl]-piperidine;1-[(3-chlorophenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[(5-methyl-2-thienyl)methyl]-piperidine;1-[(4-bromo-2-thienyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-([2,2′-bithiophen]-5-ylmethyl)-4-(1H-imidazol-4-ylmethoxy)-piperidine;3,5-dichloro-2-[[4-(1H-imidazol-4-ylmethoxy)-1-piperidinyl]methyl]-phenol;1-[(3,4-difluorophenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(3,5-difluorophenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(6-chloro-1,3-benzodioxol-5-yl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[[4-[4-(1,1-dimethylethyl)-2-thiazolyl]phenyl]methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[(1-methyl-1H-pyrrol-2-yl)methyl]-piperidine;1H-indole,3-[[4-(1H-imidazol-4-ylmethoxy)-1-piperidinyl]methyl]-1-(phenylmethyl)-;1-[(5-chloro-2-thienyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-(1,3-benzodioxol-4-ylmethyl)-4-(1H-imidazol-4-ylmethoxy)-piperidine;2-thiophenecarbonitrile,3-[[4-[[4-(1H-imidazol-4-ylmethoxy)-1-piperidinyl]methyl]phenoxy]methyl]-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[[5-(phenylethynyl)-2-thienyl]methyl]-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[[5-(4-nitrophenyl)-2-furanyl]methyl]-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[[5-(5-(3-nitrophenyl)-2-furanyl]methyl]-piperidine;1-[(4-chloro-1H-pyrazol-3-yl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(4-bromo-1-methyl-1H-pyrazol-3-yl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(4-bromo-1H-pyrazol-3-yl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;2-[[4-(1H-imidazol-4-ylmethoxy)-1-piperidinyl]methyl]-benzonitrile;4-(1H-imidazol-4-ylmethoxy)-1-[(4-iodophenyl)methyl]-piperidine;1-[(5-ethyl-2-thienyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[[5-(methylthio)-2-thienyl]methyl]-piperidine;1-[[1-(3,5-dichlorophenyl)-1H-pyrrol-2-yl]methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[[1-(4-chlorophenyl)-IH-pyrrol-2-yl]methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[[4-(phenylethynyl)-2-thienyl]methyl]-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[(3-phenoxy-2-thienyl)methyl]-piperidine;1-[[2-chloro-5-(trifluoromethyl)phenyl]methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[(4-propoxyphenyl)methyl]-piperidine;2-[[4-(1H-imidazol-4-ylmethoxy)-1-piperidinyl]methyl]-phenol;1-[(2,4-difluorophenyl) methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;3-[[4-(1H-imidazol-4-ylmethoxy)-1-piperidinyl]methyl]-2-thiophenecarbonitrile;1-(benzolb] thien-3-ylmethyl)-4-(IH-imidazol-4-ylmethoxy)-piperidine;2-chloro-3-[[4-(1H-imidazol-4-ylmethoxy)-1-piperidinyl]methyl]-pyridine;3-[[4-(1H-imidazol-4-ylmethoxy)-1-piperidinyl]methyl]-2-(2-propenyl)-phenol; 1-[(4-chloro-3-fluorophenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[[4-(trifluoromethoxy)phenyl]methyl]-piperidine;1-[(2,6-difluorophenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(4-bromo-2-fluorophenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;1-[(4-butoxyphenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;4-(1H-imidazol-4-ylmethoxy)-1-[(2,3,5-trichlorophenyl)methyl]-piperidine;1-[(2,5-dichlorophenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidine;4-(H-imidazol-4-ylmethoxy)-1-[[2-(trifluoromethyl)phenyl)methyl]-piperidine,or1-[(4-chloro-2-nitrophenyl)methyl]-4-(1H-imidazol-4-ylmethoxy)-piperidineor pharmaceutically acceptable salts or solvates thereof.

In another embodiment, selective Histamine H4 antagonists are selectedfrom those described in the international Patent ApplicationWO2009107767.

In a particular embodiment, the Histamine H4 receptor antagonist is1-[(5-chloro-1H-benzimidazol-2-yl)carbonyl]-4-methylpiperazine (alsonamed JNJ 10191584 or VUF 6002) described by Herman D. et al. (2005).This selective antagonist binds with high affinity the human HistamineH4 receptor (Ki =26 nM). This affinity is 540-fold more selective overthe H3 receptor (Ki =14.1 μM) (Zhang M. et al. 2007).

In a particular embodiment, the selective Histamine H4 receptorantagonist is 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine(also named JNJ 7777120) described by Robin L. et al. (2004).

In a particular embodiment, the selective Histamine H4 receptorantagonist is4-((3R)-3-Aminopyrrolidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine(also named A-943931) described by Cowart M D. et al. (2008).

In a particular embodiment, the selective Histamine H4 receptorantagonist iscis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine(also named A-987306) described by Liu H et al. (2008).

In another embodiment the selective Histamine H4 receptor antagonist mayconsist in an antibody (the term including antibody fragment) that canblock Histamine H4 receptor activation.

In particular, the selective Histamine H4 receptor antagonist mayconsist in an antibody directed against the Histamine H4 receptor or aligand of the Histamine H4 receptor, in such a way that said antibodyimpairs the binding of a H4 ligand to said receptor.

Antibodies directed against the Histamine H4 receptor can be raisedaccording to known methods by administering the appropriate antigen orepitope to a host animal selected, e.g., from pigs, cows, horses,rabbits, goats, sheep, and mice, among others. Various adjuvants knownin the art can be used to enhance antibody production. Althoughantibodies useful in practicing the invention can be polyclonal,monoclonal antibodies are preferred. Monoclonal antibodies againstHistamine H4 receptor or ligands of Histamine H4 receptors can beprepared and isolated using any technique that provides for theproduction of antibody molecules by continuous cell lines in culture.Techniques for production and isolation include but are not limited tothe hybridoma technique originally described by Kohler and Milstein(1975); the human B-cell hybridoma technique (Cote et al., 1983); andthe EBV-hybridoma technique (Cole et al. 1985). Alternatively,techniques described for the production of single chain antibodies (see,e.g., U.S. Pat. No. 4,946,778) can be adapted to produce anti-H4, oranti-H4 ligands single chain antibodies. Histamine H4 receptorantagonists useful in practicing the present invention also includeanti-H4, or anti-H4 ligands antibody fragments including but not limitedto F(ab′)₂ fragments, which can be generated by pepsin digestion of anintact antibody molecule, and Fab fragments, which can be generated byreducing the disulfide bridges of the F(ab′)₂ fragments. Alternatively,Fab and/or scFv expression libraries can be constructed to allow rapididentification of fragments having the desired specificity to HistamineH4 receptor.

Humanized anti-Histamine H4 receptor or anti-H4 ligands antibodies andantibody fragments therefrom can also be prepared according to knowntechniques. “Humanized antibodies” are forms of non-human (e.g., rodent)chimeric antibodies that contain minimal sequence derived from non-humanimmunoglobulin. For the most part, humanized antibodies are humanimmunoglobulins (recipient antibody) in which residues from ahypervariable region (CDRs) of the recipient are replaced by residuesfrom a hypervariable region of a non-human species (donor antibody) suchas mouse, rat, rabbit or nonhuman primate having the desiredspecificity, affinity and capacity. In some instances, framework region(FR) residues of the human immunoglobulin are replaced by correspondingnon-human residues. Furthermore, humanized antibodies may compriseresidues that are not found in the recipient antibody or in the donorantibody. These modifications are made to further refine antibodyperformance. In general, the humanized antibody will comprisesubstantially all of at least one, and typically two, variable domains,in which all or substantially all of the hypervariable loops correspondto those of a non-human immunoglobulin and all or substantially all ofthe FRs are those of a human immunoglobulin sequence. The humanizedantibody optionally also will comprise at least a portion of animmunoglobulin constant region (Fc), typically that of a humanimmunoglobulin. Methods for making humanized antibodies are described,for example, by Winter (U.S. Pat. No. 5,225,539) and Boss (Celltech,U.S. Pat. No. 4,816,397).

Then after raising antibodies directed against the Histamine H4 receptoras above described, the skilled man in the art can easily select thoseblocking Histamine H4 receptor activation.

In another embodiment the selective Histamine H4 receptor antagonist isan aptamer. Aptamers are a class of molecule that represents analternative to antibodies in term of molecular recognition. Aptamers areoligonucleotide or oligopeptide sequences with the capacity to recognizevirtually any class of target molecules with high affinity andspecificity. Such ligands may be isolated through Systematic Evolutionof Ligands by EXponential enrichment (SELEX) of a random sequencelibrary, as described in Tuerk C. and Gold L., 1990. The random sequencelibrary is obtainable by combinatorial chemical synthesis of DNA. Inthis library, each member is a linear oligomer, eventually chemicallymodified, of a unique sequence. Possible modifications, uses andadvantages of this class of molecules have been reviewed in Jayasena S.D., 1999. Peptide aptamers consists of a conformationally constrainedantibody variable region displayed by a platform protein, such as E.coli Thioredoxin A that are selected from combinatorial libraries by twohybrid methods (Colas et al., 1996).

Then after raising aptamers directed against the Histamine H4 receptoras above described, the skilled man in the art can easily select thoseblocking Histamine H4 receptor activation.

Another aspect of the invention relates to the use of an inhibitor ofHistamine H4 receptor gene expression.

Histamine receptor (H1, H2, H3 or H4) sequences showing low sequenceidentity, the inhibitors of Histamine H4 receptor gene expression whichmay be used according to the invention advantageously provides selectiveinhibition of Histamine H4 receptor gene expression, by comparison withthe other histamine receptors (H1, H2, or H3) expression.

Inhibitors of Histamine H4 receptor gene expression for use in thepresent invention may be based on anti-sense oligonucleotide constructs.Anti-sense oligonucleotides, including anti-sense RNA molecules andanti-sense DNA molecules, would act to directly block the translation ofHistamine H4 receptor mRNA by binding thereto and thus preventingprotein translation or increasing mRNA degradation, thus decreasing thelevel of Histamine H4 receptors, and thus activity, in a cell. Forexample, antisense oligonucleotides of at least about 15 bases andcomplementary to unique regions of the mRNA transcript sequence encodingHistamine H4 receptor can be synthesized, e.g., by conventionalphosphodiester techniques and administered by e.g., intravenousinjection or infusion. Methods for using antisense techniques forspecifically inhibiting gene expression of genes whose sequence is knownare well known in the art (e.g. see U.S. Pat. Nos. 6,566,135; 6,566,131;6,365,354; 6,410,323; 6,107,091; 6,046,321; and 5,981,732).

Small inhibitory RNAs (siRNAs) can also function as inhibitors ofHistamine H4 receptor gene expression for use in the present invention.Histamine H4 receptor gene expression can be reduced by contacting asubject or cell with a small double stranded RNA (dsRNA), or a vector orconstruct causing the production of a small double stranded RNA, suchthat Histamine H4 receptor gene expression is specifically inhibited(i.e. RNA interference or RNAi). Methods for selecting an appropriatedsRNA or dsRNA-encoding vector are well known in the art for genes whosesequence is known (e.g. see Tuschl, T. et al. (1999); Elbashir, S. M. etal. (2001); Hannon, G J. (2002); McManus, M T. et al. (2002);Brummelkamp, T R. et al. (2002); U.S. Pat. Nos. 6,573,099 and 6,506,559;and International Patent Publication Nos. WO01/36646, WO99/32619, and WO01/68836).

Ribozymes can also function as inhibitors of Histamine H4 receptor geneexpression for use in the present invention. Ribozymes are enzymatic RNAmolecules capable of catalyzing the specific cleavage of RNA. Themechanism of ribozyme action involves sequence specific hybridization ofthe ribozyme molecule to complementary target RNA, followed byendonucleolytic cleavage. Engineered hairpin or hammerhead motifribozyme molecules that specifically and efficiently catalyzeendonucleolytic cleavage of Histamine H4 receptor mRNA sequences arethereby useful within the scope of the present invention. Specificribozyme cleavage sites within any potential RNA target are initiallyidentified by scanning the target molecule for ribozyme cleavage sites,which typically include the following sequences, GUA, GUU, and GUC. Onceidentified, short RNA sequences of between about 15 and 20ribonucleotides corresponding to the region of the target genecontaining the cleavage site can be evaluated for predicted structuralfeatures, such as secondary structure, that can render theoligonucleotide sequence unsuitable. The suitability of candidatetargets can also be evaluated by testing their accessibility tohybridization with complementary oligonucleotides, using, e.g.,ribonuclease protection assays.

Both antisense oligonucleotides and ribozymes useful as inhibitors ofHistamine H4 receptor gene expression can be prepared by known methods.These include techniques for chemical synthesis such as, e.g., by solidphase phosphoramadite chemical synthesis. Alternatively, anti-sense RNAmolecules can be generated by in vitro or in vivo transcription of DNAsequences encoding the RNA molecule. Such DNA sequences can beincorporated into a wide variety of vectors that incorporate suitableRNA polymerase promoters such as the T7 or SP6 polymerase promoters.Various modifications to the oligonucleotides of the invention can beintroduced as a means of increasing intracellular stability andhalf-life. Possible modifications include but are not limited to theaddition of flanking sequences of ribonucleotides ordeoxyribonucleotides to the 5′ and/or 3′ ends of the molecule, or theuse of phosphorothioate or 2′-O-methyl rather than phosphodiesteraselinkages within the oligonucleotide backbone.

Antisense oligonucleotides siRNAs and ribozymes of the invention may bedelivered in vivo alone or in association with a vector. In its broadestsense, a “vector” is any vehicle capable of facilitating the transfer ofthe antisense oligonucleotide siRNA or ribozyme nucleic acid to thecells and preferably cells expressing Histamine H4 receptor. Preferably,the vector transports the nucleic acid to cells with reduced degradationrelative to the extent of degradation that would result in the absenceof the vector. In general, the vectors useful in the invention include,but are not limited to, plasmids, phagemids, viruses, other vehiclesderived from viral or bacterial sources that have been manipulated bythe insertion or incorporation of the the antisense oligonucleotidesiRNA or ribozyme nucleic acid sequences. Viral vectors are a preferredtype of vector and include, but are not limited to nucleic acidsequences from the following viruses: retrovirus, such as moloney murineleukemia virus, harvey murine sarcoma virus, murine mammary tumor virus,and rouse sarcoma virus; adenovirus, adeno-associated virus; SV40-typeviruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses;herpes virus; vaccinia virus; polio virus; and RNA virus such as aretrovirus. One can readily employ other vectors not named but known tothe art.

Preferred viral vectors are based on non-cytopathic eukaryotic virusesin which non-essential genes have been replaced with the gene ofinterest. Non-cytopathic viruses include retroviruses (e.g.,lentivirus), the life cycle of which involves reverse transcription ofgenomic viral RNA into DNA with subsequent proviral integration intohost cellular DNA. Retroviruses have been approved for human genetherapy trials. Most useful are those retroviruses that arereplication-deficient (i.e., capable of directing synthesis of thedesired proteins, but incapable of manufacturing an infectiousparticle). Such genetically altered retroviral expression vectors havegeneral utility for the high-efficiency transduction of genes in vivo.Standard protocols for producing replication-deficient retroviruses(including the steps of incorporation of exogenous genetic material intoa plasmid, transfection of a packaging cell lined with plasmid,production of recombinant retroviruses by the packaging cell line,collection of viral particles from tissue culture media, and infectionof the target cells with viral particles) are provided in Kriegler, 1990and in Murry, 1991).

Preferred viruses for certain applications are the adeno-viruses andadeno-associated viruses, which are double-stranded DNA viruses thathave already been approved for human use in gene therapy. Theadeno-associated virus can be engineered to be replication deficient andis capable of infecting a wide range of cell types and species. Itfurther has advantages such as, heat and lipid solvent stability; hightransduction frequencies in cells of diverse lineages, includinghemopoietic cells; and lack of superinfection inhibition thus allowingmultiple series of transductions. Reportedly, the adeno-associated viruscan integrate into human cellular DNA in a site-specific manner, therebyminimizing the possibility of insertional mutagenesis and variability ofinserted gene expression characteristic of retroviral infection. Inaddition, wild-type adeno-associated virus infections have been followedin tissue culture for greater than 100 passages in the absence ofselective pressure, implying that the adeno-associated virus genomicintegration is a relatively stable event. The adeno-associated virus canalso function in an extrachromosomal fashion.

Other vectors include plasmid vectors. Plasmid vectors have beenextensively described in the art and are well known to those of skill inthe art. See e.g. Sambrook et al., 1989. In the last few years, plasmidvectors have been used as DNA vaccines for delivering antigen-encodinggenes to cells in vivo. They are particularly advantageous for thisbecause they do not have the same safety concerns as with many of theviral vectors. These plasmids, however, having a promoter compatiblewith the host cell, can express a peptide from a gene operativelyencoded within the plasmid. Some commonly used plasmids include pBR322,pUC18, pUCI9, pRC/CMV, SV40, and pBlueScript. Other plasmids are wellknown to those of ordinary skill in the art. Additionally, plasmids maybe custom designed using restriction enzymes and ligation reactions toremove and add specific fragments of DNA. Plasmids may be delivered by avariety of parenteral, mucosal and topical routes. For example, the DNAplasmid can be injected by intramuscular, intradermal, subcutaneous, orother routes. It may also be administered by intranasal sprays or drops,rectal suppository and orally. It may also be administered into theepidermis or a mucosal surface using a gene-gun. The plasmids may begiven in an aqueous solution, dried onto gold particles or inassociation with another DNA delivery system including but not limitedto liposomes, dendrimers, cochleate and microencapsulation.

Another object of the invention relates to a method for treating and/orpreventing vestibular disorders comprising administering a subject inneed thereof with a selective Histamine H4 receptor antagonist or aninhibitor of Histamine H4 receptor gene expression.

Selective Histamine H4 receptor antagonists or inhibitors of HistamineH4 receptor gene expression may be administered in the form of apharmaceutical composition, as defined below.

Preferably, said antagonists or inhibitors are administered in atherapeutically effective amount.

By a “therapeutically effective amount” is meant a sufficient amount ofthe selective Histamine H4 receptor antagonist or inhibitor of HistamineH4 receptor gene expression to treat and/or to prevent vestibulardisorders at a reasonable benefit/risk ratio applicable to any medicaltreatment.

It will be understood that the total daily usage of the compounds andcompositions of the present invention will be decided by the attendingphysician within the scope of sound medical judgment. The specifictherapeutically effective dose level for any particular patient willdepend upon a variety of factors including the disorder being treatedand the severity of the disorder; activity of the specific compoundemployed; the specific composition employed, the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidential with the specific polypeptide employed; and like factorswell known in the medical arts. For example, it is well within the skillof the art to start doses of the compound at levels lower than thoserequired to achieve the desired therapeutic effect and to graduallyincrease the dosage until the desired effect is achieved. However, thedaily dosage of the products may be varied over a wide range from 0.01to 1,000 mg per adult per day. Preferably, the compositions contain0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250and 500 mg of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. A medicament typically containsfrom about 0.01 mg to about 500 mg of the active ingredient, preferablyfrom 1 mg to about 100 mg of the active ingredient. An effective amountof the drug is ordinarily supplied at a dosage level from 0.0002 mg/kgto about 20 mg/kg of body weight per day, especially from about 0.001mg/kg to 7 mg/kg of body weight per day.

Screening Methods

Inhibitors of the invention can be further identified by screeningmethods described in the state of the art. The screening methods of theinvention can be carried out according to known methods.

The screening method may measure the binding of a candidate compound tothe receptor, or to cells or membranes bearing the receptor, or a fusionprotein thereof by means of a label directly or indirectly associatedwith the candidate compound. Alternatively, a screening method mayinvolve measuring or, qualitatively or quantitatively, detecting thecompetition of binding of a candidate compound to the receptor with alabelled competitor (e.g., antagonist or agonist). Further, screeningmethods may test whether the candidate compound results in a signalgenerated by an antagonist of the receptor, using detection systemsappropriate to cells bearing the receptor. Antagonists can be assayed inthe presence of a known agonist (e.g. Histamine) and an effect onactivation by the agonist by the presence of the candidate compound isobserved. Competitive binding using known agonist such as histamine isalso suitable.

The antagonistic activity of the candidate compounds towards theHistamine H4 receptor may be for example determined using variousmodels. For example, methods that are described in Thurmond R L et al.(2004) or Venable J D. et al. (2005) may be used.

Pharmaceutical Compositions

The selective Histamine H4 receptor antagonists or inhibitors ofHistamine H4 receptor gene expression may be combined withpharmaceutically acceptable excipients, and optionally sustained-releasematrices, such as biodegradable polymers, to form therapeuticcompositions.

In the pharmaceutical compositions of the present invention, the activeprinciple, alone or in combination with another active principle, can beadministered in a unit administration form, as a mixture withconventional pharmaceutical supports, to animals and human beings.Suitable unit administration forms comprise oral-route forms such astablets, gel capsules, powders, granules and oral suspensions orsolutions, sublingual and buccal administration forms, aerosols,implants, subcutaneous, transdermal, topical, intraperitoneal,intramuscular, intravenous, subdermal, transdermal, intrathecal andintranasal administration forms and rectal administration forms.

Preferably, the pharmaceutical compositions contain vehicles which arepharmaceutically acceptable for a formulation capable of being injected.These may be in particular isotonic, sterile, saline solutions(monosodium or disodium phosphate, sodium, potassium, calcium ormagnesium chloride and the like or mixtures of such salts), or dry,especially freeze-dried compositions which upon addition, depending onthe case, of sterilized water or physiological saline, permit theconstitution of injectable solutions.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions; formulations including sesame oil,peanut oil or aqueous propylene glycol; and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms, such as bacteria and fungi.

Solutions comprising compounds of the invention as free base orpharmacologically acceptable salts can be prepared in water suitablymixed with a surfactant, such as hydroxypropylcellulose. Dispersions canalso be prepared in glycerol, liquid polyethylene glycols, and mixturesthereof and in oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms.

The selective Histamine H4 receptor antagonists or inhibitors ofHistamine H4 receptor gene expression of the invention can be formulatedinto a composition in a neutral or salt form. Pharmaceuticallyacceptable salts include the acid addition salts (formed with the freeamino groups of the protein) and which are formed with inorganic acidssuch as, for example, hydrochloric or phosphoric acids, or such organicacids as acetic, oxalic, tartaric, mandelic, and the like. Salts formedwith the free carboxyl groups can also be derived from inorganic basessuch as, for example, sodium, potassium, ammonium, calcium, or ferrichydroxides, and such organic bases as isopropylamine, trimethylamine,histidine, procaine and the like.

The carrier can also be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetables oils. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, by the maintenanceof the required particle size in the case of dispersion and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminiummonostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activepolypeptides in the required amount in the appropriate solvent withvarious of the other ingredients enumerated above, as required, followedby filtered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Upon formulation, solutions will be administered in a manner compatiblewith the dosage formulation and in such amount as is therapeuticallyeffective. The formulations are easily administered in a variety ofdosage forms, such as the type of injectable solutions described above,but drug release capsules and the like can also be employed.

For parenteral administration in an aqueous solution, for example, thesolution should be suitably buffered if necessary and the liquid diluentfirst rendered isotonic with sufficient saline or glucose. Theseparticular aqueous solutions are especially suitable for intravenous,intramuscular, subcutaneous and intraperitoneal administration. In thisconnection, sterile aqueous media which can be employed will be known tothose of skill in the art in light of the present disclosure. Forexample, one dosage could be dissolved in 1 ml of isotonic NaCl solutionand either added to 1000 ml of hypodermoclysis fluid or injected at theproposed site of infusion. Some variation in dosage will necessarilyoccur depending on the condition of the subject being treated. Theperson responsible for administration will, in any event, determine theappropriate dose for the individual subject.

The selective Histamine H4 receptor antagonists or inhibitors ofHistamine H4 receptor gene expression of the invention may be formulatedwithin a therapeutic mixture to comprise about 0.0001 to 1.0 milligrams,or about 0.001 to 0.1 milligrams, or about 0.1 to 1.0 or even about 10milligrams per dose or so. Multiple doses can also be administered.

In addition to the compounds of the invention formulated for parenteraladministration, such as intravenous or intramuscular injection, otherpharmaceutically acceptable forms include, e.g. tablets or other solidsfor oral administration; liposomal formulations; time release capsules;and any other form currently used.

In a particular embodiment, the selective Histamine H4 receptorantagonists or inhibitors of Histamine H4 receptor gene expression areadministered directly in the inner ear through the tympanic membrane.This administration mode may be preferred for introducing a direct andlong term effect on the vestibule. Accordingly in a preferredembodiment, the selective Histamine H4 receptor antagonists orinhibitors of Histamine H4 receptor gene expression are administered ina gel formulation to allow a long term release of said antagonists orinhibitors in the inner ear.

The invention will further be illustrated in view of the followingfigures and examples.

FIGURES

FIG. 1. Effect of VUF 6002 on the depolarization-induced firing volley.(A) Representative traces obtained in an individual neuron after anapplication of 100 μM VUF 6002 (A), 10 μm (B) and 1 μM (C). Theinhibitory responses were reversed during rinse with control medium.Inserts show individual volley before (a), during (b) and after (c) theapplication of VUF 6002.

FIG. 2. Dose-dependent effect of VUF 6002 on the firing volley inducedby standard depolarization. Curve fitting with one-term Hill equation(black line) gives an IC50 of 5.8 μM. Data are the mean percentageinhibition of control responses. Number of experiments are indicatedabove error bars.

FIG. 3. Effect of betahistine on the depolarization-induced firingvolley. Representative traces obtained in an individual neuron after anapplication of 5 mM betahistine. Inserts show individual volley before(a), during (b) and after (c) the application of betahistine. Note thestrong depolarization of about 15 mV induced by betahistine. Theseresponses were rapidly reversed during rinse with control medium.

FIG. 4. Effect of VUF 6002, betahistidine and thioperamide on thevariation of membrane potentials. Although VUF 6002 did not inducemembrane variations, the two other compounds generated strongdepolarisations at high concentrations. Stars indicate concentrationsinducing 90% inhibition of the firing.

EXAMPLE

Methods:

Drugs/Chemicals: The 1-[(5-Chloro-1H-benzimidazol-2-yl)carbonyl]-4-methyl piperazine maleate (JNJ 10191584 maleate or VUF 6002)was purchase from Tocris Bioscience (Bristol, UK), and the1-[(5-chloro-1H-indol-2-yl) carbonyl]-4-methyl piperazine maleate (JNJ7777120) was obtained from Sigma (Sigma-Aldrich, St-Quentin Fallavier,France). Stock solutions were prepared at 50 mM in 100% dimethylsulfoxide as recommended by the suppliers. Stock solutions ofbetahistine dihydrochloride (purchased from Sigma-Aldrich, St-QuentinFallavier, France) andN-cyclohexyl-4-(1H-imidazol-4-yl)-1-piperidinecarbothioamide maleate(thioperamide, Sigma-Aldrich) were prepared in recording medium atrespectively 1 M and 0.01 M. Drugs were then diluted in working solutionbefore use.

Cell culture: Vestibular ganglion neurons were explanted asepticallyfrom 2 to 6 days-old Wistar rats (Centre d'Elevage Janvier, LeGenest-Saint-Isle, France). All procedures were carried out inaccordance to the French/European Communities Council Directive86/609/EEC. The brainstem was hemi-sectioned and the eighth nerve wasfollowed up to the level of the otocyst and cut just rostral to it.

The vestibular ganglia were excised, placed in Leibovitz medium (L15,Invitrogen, Cergy Pontoise, France), and dissociated by enzymatically(collagenase 0.75 mg/ml, dispase 1 mg/ml and dnase 0.75 mg/ml, 15 min at25° C.). Enzymes were washed with Tyrode solution without Ca²⁺ and Mg²⁺,and the ganglion neurons were gently dissociated in culture medium witha pipette. The neurons were plated onto culture dishes previously coatedwith 5 μg/ml poly-L-ornithine, 10 μg/ml laminin and subsequently filledwith 0.5 ml of a 1:1 mixture of Dulbecco's modified eagle medium andHam's F-12 medium (Invitrogen) supplemented with 2% N₂ nutrient glucose(5 g/l), glutamine (1.5 mM), sodium bicarbonate (1.1 g/l), HEPES buffer(15 mM, pH 7.4), AraC 2 μM, brain-derived neurotrophic factor 10 μg/mland 1% penicillin/streptomycin. The low density cultures were thenmaintained at 37° C. in 5% CO₂ for 7 to 8 days prior patch-clampexperiments.

Patch-clamp recordings: Whole-cell (current-clamp configuration)recording of responses were obtained using an Axopatch 200B amplifier(Axon Instruments; Molecular Devices Corp., Sunnyvale, Calif., USA). Theextracellular solution contained (in mM): NaCl 135, HEPES 10, glucose10, MgCl₂ 1, KCl 5, and CaCl₂ 4, pH 7.35 (with NaOH). Recording pipettes(2-3 MΩ) were drawn from microhematocrit tubes (Modulohm I/S Herlev,Denmark) and filled with the following solution (in mM): KCl 135, HEPES10,glucose 10, NaCl5, EGTA 5, Mg-ATP3, GTP-Na 1, pH 7.35 (with KOH). Theosmolarity of all solutions was set to 300 mOsm/I⁻¹. Experimentalparameters and data acquisition were controlled with a PC computer and aTecmar Labmaster analogue interface (Axon instruments, CA). Voltagetransients were recorded from neurons presenting resting potentialslying between −45 and −65 mV. Trains of action potentials (APs) wereelicited using 1 s, 200 pA depolarizing pulses applied every 6.5 s.Current signals were filtered at 10 KHz, digitized and stored usingpCLAMP software (v 10.2, Axon instruments).

Drug application : The control and test solutions were applied using amultiple capillary perfusion system (flow rate 500 μl/min). After eachapplication of the tested drug, the cells were washed with controlbuffer.

Data analysis and statistical methods : The results are expressed asmeans±S.E.M. The number of sample size (n) given is the number ofneurons tested. Variations of the membrane potential and the number ofAPs were analysed using pCLAMP software (v10.2, Axon instruments). Drugconcentration-effect relationships were fitted with a Hill equation ofthe form I(x)=A*xn/(IC₅₀n+xn).

Results :

Immunochemical studies conducted by Western-blot andimunohistochemistry, using antibodies binding Histamine H4 receptor,revealed respectively the presence of Histamine H4 receptor protein inthe primary vestibular ganglion and identified its cellular location tothe membrane of neurones (data not shown).

Under phase contrast microscopy, cultured vestibular ganglion neuronshad refringent soma with diameters ranging between 10 and 25 μm. Allrecorded neurons had long neuritic processes.

Recorded neurons displayed a resting potential of −50.3±3.6 mV (n=116,range−45 to −65 mV). Upon application of depolarizing pulses (1 s, 200pA) two types of APs discharging volley were recorded. Phasic dischargesconstituted of 1 to 4 AP, while tonic discharges exhibited 10 to 80 APs(mean 29.3±14.3, n=92), (FIG. 1A-C a). Unless inhibitors application,these discharging patterns could be stable up to 30 minutes.

When the discharge pattern was phasic, application of 1 mM VUF 6002completely abolished the firing (n=6). In neurons exhibiting tonicresponses, application of VUF 6002 reduced the number of elicited APs indose-dependant way. FIG. 1 illustrates the inhibitions of the discharge.At 100 μM the inhibition was 91% (FIG. 1A), while the compound inducedonly a slight membrane hyperpolarization (about −3 mV) (FIG. 4).

Application of 10 μm, 1 μM and 100 nM of VUF 6002 inhibited the firingby 55% (n=6), 37% (n=11) and 20% (n=10) respectively. These inhibitoryeffects were totally reversed by subsequent perfusion of control mediumdemonstrating the reversibility of the response (FIG. 1B-C). Actionpotentials intrinsic properties, such as spike amplitude, time to peak,rise and decay time constants, appeared to be not affected by VUF 6002.

The effect of another H4 receptor antagonist, the JNJ 7777120, was alsostudied. JNJ 7777120 was less efficient at low concentration (3%inhibition at 100 nM, n=7) than VUF 6002 while at higher concentrationsthe differences were not significant (p>0.05) (29% at 1 μM, n=7; 41% at10 μM, n=9). Moreover, the 7777120 did not induce membranedepolarisation, even for high concentration application (1 mM).

The dose-response inhibition relationship of VUF 6002 was constructedwith concentrations between 1 nM and 1 mM (FIG. 2). In our recordingconditions, maximum inhibition occurred around 100 μM (90% inhibition)and the dose-response relationship had an IC₅₀ of 5.8 μM.

Dose-response inhibition relationship calculated for the JNJ 7777120between 0.1 μM and 1000 μM gave an IC₅₀ of 10 μM.

The two selective H4 receptor antagonists VUF 6002 and JNJ 7777120exhibit quite similar effects on both the firing and variation inmembrane potentials.

By comparison, responses were established for applications of BH, anantagonist of the Histamine H3 receptor (Arrang et al, 1985). BHinhibited the discharge volley in the same way. Maximum inhibition ofthe discharge volley, elicited during standard depolarizationstimulation, by BH was around 10 mM. During 2 mM application themembrane potential was not affected, but treatment by BH at 5 mM induceda strong depolarization of the neurons (14.3±4.7 mV, n=16) (FIG. 3, FIG.4). The firing inhibition and depolarisation were rapidly abolished bysubsequent perfusion of control medium indicating the reversibility ofthe response (FIG. 3). The dose-response relationship presented an IC₅₀of 2.2 mM.

Thioperamide, a histamine antagonist of both H3 and H4 receptors (Gbahouet al. 2005) was tested on cultured vestibular neurons. At lowconcentration (0.01 to 10 μM), thioperamide inhibited the dischargevolley without depolarizing the neurons (10% at 0.1 μM and 24% at 10 μM,n=9 and 13 respectively). Conversely, higher concentrations blocked theactivity (87% at 500 μM, n=10) followed by strong membranedepolarisations of the neurons (FIG. 4). The firing inhibition bythioperamide applications was only slightly reversible during rinse,especially for high concentrations. The dose-response relationshippresented an IC₅₀ of 100 μM.

Thioperamide exhibits effects lying between those of VUF 6002 and BH.

Present results are the first demonstration that selective Histamine H4receptor antagonists are potent inhibitors of the mammal vestibularprimary neurons firing.

-   -   Selective Histamine H4 receptor antagonists inhibit reversibly        and on a dose-dependant manner the firing of vestibular neurons        without inducing membrane depolarisations.    -   Betahistine (H3 antagonist) and thioperamide (H3 and H4        antagonist, ie non-selective Histamine H4 receptor antagonist)        inhibit the firing on vestibular neurons, but their use request        high concentration to get comparable responses as those of the        selective Histamine H4 receptor antagonists. At these high        concentrations, betahistine and thioperamide induce pronounced        depolarisation of the neurons. Moreover, the application of        thioperamide is only slightly reversible.    -   Selective Histamine H4 receptor antagonists are more efficient        than classical antivertiginous prescribed drugs.    -   The pharmacological properties of selective Histamine H4        receptor antagonists designs it as a powerful vestibuloplegic        drug that could bring a therapeutic gain in the treatment of        vestibular disorders.

Accordingly, selective inhibitors of Histamine H4 receptor geneexpression and/or activity may be useful for the treatment of vestibulardisorders.

REFERENCES

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The invention claimed is:
 1. A method for treating a vestibular disorderin a subject in need thereof, comprising administering a selectiveHistamine H4 receptor antagonist to the subject, whereby treatment ofthe vestibular disorder, alleviates the progress of said vestibulardisorder or of at least one symptom of said vestibular disorder, whereinthe Histamine H4 receptor antagonist is selected from the groupconsisting of2-isobutyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine andderivatives thereof, and wherein derivatives of2-isobutyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine areselected from the group consisting of2-(4-fluorobenzyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine,2-cyclopropyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine,2-tert-butyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine,2-isopropyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine,2-(cyclopropylmethyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine,6-(3-(methylamino)azetidin-1-yl)-2-(phenoxymethyl)pyrimidin-4-amine,6-(3-aminoazetidin-1-yl)-2-isobutylpyrimidin-4-amine,2-isobutyl-6-(3-methyl-3-(methylamino)azetidin-1-yl)pyrimidin-4-amine,2-cyclobutyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine,2-cyclopentyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine,2-(2,2-dimethylpropyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine,2-cyclohexylmethyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine and2-cyclohexyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine.
 2. Themethod according to claim 1, wherein said vestibular disorder isselected from the group consisting of vestibular neuritis, spell ofMénière's disease, endolymphatic hydrops, barotraumatism with vestibulardisorders, vestibular syndromes after autoimmune inner ear disease,vestibular syndromes after chirurgical treatments of middle ear, chronicMenière, Menière's disease, vestibular schwannomas and vestibularataxia.
 3. The method according to claim 1, wherein said selective H4receptor antagonist is systemically administered.
 4. The methodaccording to claim 1, wherein said at least one symptom is selected fromthe group comprising vertigo, dizziness, imbalance and nausea.
 5. Themethod according to claim 1, wherein said vestibular disorder is spellof Ménière's disease or chronic Menière's disease.